Methods of stimulating appetite and / or increasing body weight in subjects suffering from fibrotic disease using non-naturally occurring melanocortin analogs

Abstract

The present invention provides methods of using non-naturally occurring melanocortin analogs to increase body weight and / or increase food consumption in a subject having a kidney disease and / or a liver disease (e.g., chronic kidney disease, renal failure, non-alcoholic fatty liver disease (NAFLD)). Also provided are methods of stimulating appetite in a subject via administration of a non-naturally occurring melanocortin analogue. The non-naturally occurring melanocortin analogs may be present in pharmaceutical compositions and delivered via parenteral administration (e.g., subcutaneous injection). The methods improve appetite, increase food consumption, increase body weight, muscle mass, and / or fat mass in the subject.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 486,232, filed February 21, 2023, and U.S. Provisional Patent Application No. 63 / 541,394, filed September 29, 2023, which are incorporated herein by reference in their entirety.

[0003] By referencing the merged sequence list

[0004] This application contains a sequence list conforming to the ST.26 standard, which was filed concurrently with the Patent Centre in XML format and is hereby incorporated by reference in its entirety. A copy of the .xml file created on February 16, 2024, is named 146316_8006_WO00_SL.xml and has a size of 1,552,278 bytes. Background Technology

[0005] Melanocortin analogues have been synthesized for potential treatment of a variety of conditions, including weight regulation (e.g., obesity, anorexia, and cachexia), hormone secretion and multiple exocrine gland insufficiency (e.g., Sjögren's syndrome), immune-related conditions, and sexual dysfunction.

[0006] Patients with kidney disease (e.g., chronic kidney disease, kidney failure) and liver disease (e.g., non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH)) often experience symptoms such as vomiting, decreased or absent appetite, and weight loss. If left untreated, decreased or absent appetite (e.g., anorexia) can lead to fatigue, malnutrition, weight loss, reduced muscle and / or fat mass, and a decline in overall physical condition. Decreased appetite and / or weight loss are also symptoms of cachexia (wasting disease), which can negatively impact a patient's quality of life and survival. These symptoms and cachexia may prevent patients from receiving appropriate treatment or may reduce the duration or intensity of treatment for kidney and / or liver disease.

[0007] Despite recent progress, more effective treatments for decreased appetite and / or weight loss in patients with kidney and / or liver disease remain to be developed. Appetite stimulation methods that can effectively promote appetite, increase food consumption, and increase weight (e.g., muscle mass, fat mass) in patients with kidney and / or liver disease are also needed. Such treatments could be more easily tolerated and beneficial for patients treating kidney and / or liver disease. Summary of the Invention

[0008] In some embodiments, the present invention includes a method for stimulating the appetite and / or increasing the weight of a subject suffering from kidney disease and / or liver disease, the method comprising:

[0009] The subject was administered a therapeutically effective amount of a non-naturally occurring melanocortin analogue, which comprises the sequence according to formula (I).

[0010] X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I)

[0011] in:

[0012] R 1 The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), trans-4-guanidino-proline (transPro(guan)), cis-4-guanidino-proline (cisPro(guan)), acetylated trans-4-guanidino-proline (Ac-transPro(guan)), acetylated cis-4-guanidino-proline (Ac-cisPro(guan)), tyrosine, D-tyrosine, dimethyltyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid;

[0013] R 2The group consisting of the following is absent or selected: proline, histidine, D-hydroxyproline (dHyp), transPro(guan), cisPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, leucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine.

[0014] R 3 The group consisting of the following is absent or selected: histidine, L-proline, trans-Pro(guan), cis-Pro(guan), D-valine, glutamic acid, tryptophanyl arginine (Trp-Arg), glycine, D-leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzozazepine-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazol-(1,5-a)(1,4)diazepine-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazazepine(4,3-b)indol-3(2H)-one (Aia), octahydroindol-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), and indololin-2-carboxylic acid (Ioc).

[0015] R 4 Select the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, dBip, glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-iodo-D-phenylalanine (p(I)dPhe), p-fluoro-D-phenylalanine (p(F)dPhe), and p-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);

[0016] R 5 The following groups are not present or are selected: arginine, homoarginine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(I)dPhe;

[0017] R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-phenylalanine, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1'), Aba, Ata, D-tyrosine, Pen, dPen and D-alanine;

[0018] R 7The group consisting of the following is absent or selected: glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2') and tetrahydro-isoquinoline-3-carboxylic acid (Tic);

[0019] R 8 It may be absent or contain lysine;

[0020] R 9 To R 20 It does not exist;

[0021] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated n-leucine;

[0022] X 2 It may be absent or contain D-proline;

[0023] X 3 It does not exist;

[0024] Y 1 The group consisting of the following is absent or selected: D-valine, D-tert-leucine, L-tert-leucine, ortholeucine, and D-proline;

[0025] Y 2 The group consisting of the following is absent or selected: D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, ortholeucine, and glycine;

[0026] Y 3 The group consisting of the following is absent or selected: D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;

[0027] Y 4 It is absent or is either D-aspartic acid or aspartic acid;

[0028] Y 5 To Y 8 It does not exist;

[0029] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[0030] When R 1 For cysteine ​​and R 7 When it is cysteine, R 1 With R 7 Disulfide bonds between them;

[0031] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[0032] When R 1 Or R 2 It is glutamic acid or aspartic acid and R 7 When it is lysine or Dap, R 1 Or R 2 With R 7 The side-chain lactam bridges between them;

[0033] When R 2 For lysine and R 7 When it is glutamic acid or aspartic acid, R 2 With R 7 The side-chain lactam bridges between them;

[0034] When R 1 Or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 Or R 2 With R 8 The side-chain lactam bridges between them;

[0035] The conditions are:

[0036] When R 2 When it is dAsp, then R 7 Not for dLys;

[0037] When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7 Not Arg-Trp-Lys;

[0038] When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R4 It is dNal(2') and the C-terminus is not modified;

[0039] When R 3 For Aba, Ata, or Aia, R 6 When it is Aia, then R 4 Not dNal(2'), or R 4 For dNal(2') and R 5 Not for Arg;

[0040] When R 4 When R is p(Cl)dPhe, then 3 Not Pro or His;

[0041] When R 4 When the value is p(I)dPhe, this non-natural melanocortin analogue is obtained through R. 1 With R 7 The side-chain lactam bridged cyclization between them, and R 2 and R 3 At least one of them is Pro;

[0042] When Y 2 To Y 4 If it does not exist, then Y 1 It is absent or contains ortholeucine;

[0043] When R 2 For Pro or Y 2 When it is Hyp, then R 3 Not for Pro;

[0044] When R 3 R 5 Or R 6 If it does not exist, then this non-natural melanocortin analogue is obtained through R. 1 With R 7 The cyclization of lactams between them, or X 1 To X 2 It exists and is Ac-dVal-dPro;

[0045] When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys (SEQ ID NO:526) or Cys-Pro-dNal(2')-Arg-Trp-Cys (SEQ ID NO:527), then R 1 Not Ac-Nle or Y 1 To Y 2 Not dVal-dPro, dVal-dVal, or dPro-dPro; and

[0046] When this non-natural melanocortin analogue is administered via R 2 With R 8 When the lactam bridge between them is cyclized, then R 3 Not His or Y 1 Not dVal.

[0047] In some embodiments, the present invention includes the use of non-naturally occurring melanocortin analogues for stimulating appetite and / or increasing weight in subjects with kidney and / or liver disease.

[0048] This non-natural melanocortin analog contains a sequence according to formula (I).

[0049] X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I)

[0050] in:

[0051] R 1The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), trans-4-guanidino-proline (transPro(guan)), cis-4-guanidino-proline (cisPro(guan)), acetylated trans-4-guanidino-proline (Ac-transPro(guan)), acetylated cis-4-guanidino-proline (Ac-cisPro(guan)), tyrosine, D-tyrosine, dimethyltyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid;

[0052] R 2 The group consisting of the following is absent or selected: proline, histidine, D-hydroxyproline (dHyp), transPro(guan), cisPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, leucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine.

[0053] R 3 The group consisting of the following is absent or selected: histidine, L-proline, trans-Pro(guan), cis-Pro(guan), D-valine, glutamic acid, tryptophanyl arginine (Trp-Arg), glycine, D-leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzozazepine-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazol-(1,5-a)(1,4)diazepine-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazazepine(4,3-b)indol-3(2H)-one (Aia), octahydroindol-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), and indololin-2-carboxylic acid (Ioc).

[0054] R 4 Select the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, dBip, glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-iodo-D-phenylalanine (p(I)dPhe), p-fluoro-D-phenylalanine (p(F)dPhe), and p-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);

[0055] R 5The following groups are not present or are selected: arginine, homoarginine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(I)dPhe;

[0056] R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-phenylalanine, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1'), Aba, Ata, D-tyrosine, Pen, dPen and D-alanine;

[0057] R 7 The group consisting of the following is absent or selected: glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2') and tetrahydro-isoquinoline-3-carboxylic acid (Tic);

[0058] R 8 It may be absent or contain lysine;

[0059] R 9 To R 20 It does not exist;

[0060] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated n-leucine;

[0061] X 2 It may be absent or contain D-proline;

[0062] X 3 It does not exist;

[0063] Y 1 The group consisting of the following is absent or selected: D-valine, D-tert-leucine, L-tert-leucine, ortholeucine, and D-proline;

[0064] Y 2The group consisting of the following is absent or selected: D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, ortholeucine, and glycine;

[0065] Y 3 The group consisting of the following is absent or selected: D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;

[0066] Y 4 It is absent or is either D-aspartic acid or aspartic acid;

[0067] Y 5 To Y 8 It does not exist;

[0068] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[0069] When R 1 For cysteine ​​and R 7 When it is cysteine, R 1 With R 7 Disulfide bonds between them;

[0070] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[0071] When R 1 Or R 2 It is glutamic acid or aspartic acid and R 7 When it is lysine or Dap, R 1 Or R 2 With R 7 The side-chain lactam bridges between them;

[0072] When R 2 For lysine and R 7 When it is glutamic acid or aspartic acid, R 2 With R 7 The side-chain lactam bridges between them;

[0073] When R 1 Or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 Or R 2 With R 8 The side-chain lactam bridges between them;

[0074] The conditions are:

[0075] When R 2 When it is dAsp, then R 7 Not for dLys;

[0076] When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7 Not Arg-Trp-Lys;

[0077] When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified;

[0078] When R 3 For Aba, Ata, or Aia, R 6 When it is Aia, then R 4 Not dNal(2'), or R 4 For dNal(2') and R 5 Not for Arg;

[0079] When R 4 When R is p(Cl)dPhe, then 3 Not Pro or His;

[0080] When R 4 When the value is p(I)dPhe, this non-natural melanocortin analogue is obtained through R. 1 With R 7 The side-chain lactam bridged cyclization between them, and R 2 and R 3 At least one of them is Pro;

[0081] When Y 2 To Y 4 If it does not exist, then Y 1 It is absent or contains ortholeucine;

[0082] When R 2 For Pro or Y 2 When it is Hyp, then R 3 Not for Pro;

[0083] When R 3 R 5 Or R 6If it does not exist, then this non-natural melanocortin analogue is obtained through R. 1 With R 7 The cyclization of lactams between them, or X 1 To X 2 It exists and is Ac-dVal-dPro;

[0084] When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys or Cys-Pro-dNal(2')-Arg-Trp-Cys, then R 1 Not Ac-Nle or Y 1 To Y 2 Not dVal-dPro, dVal-dVal, or dPro-dPro; and

[0085] When this non-natural melanocortin analogue is administered via R 2 With R 8 When the lactam bridge between them is cyclized, then R 3 Not His or Y 1 Not dVal.

[0086] In some embodiments, if present, the N-terminus is modified with a functional group selected from the group consisting of: acyl groups, imine groups, amide groups, urea groups, carbamate groups, sulfonamide groups, and alkylamine groups.

[0087] In some embodiments, if present, the N-terminus is modified with an acyl group.

[0088] In some embodiments, the acyl group is an acetyl group.

[0089] In some embodiments, the acyl group is a formyl group.

[0090] In some embodiments, if present, the N-terminus is modified with an imine group.

[0091] In some embodiments, if present, the N-terminus is modified with an amide group.

[0092] In some embodiments, the amide group is a pyroglutamyl (pGlu) group.

[0093] In some embodiments, the amide group is derived from a fatty acid.

[0094] In some embodiments, the N-terminus is not modified, if present.

[0095] In some embodiments, if present, the C-terminus is modified with a functional group selected from the group consisting of amide groups, ester groups, and aldehyde groups.

[0096] In some embodiments, the C-terminus is modified with an amide group.

[0097] In some embodiments, the amide group is a -NH alkylamide group or a -NH arylamide group.

[0098] In some embodiments, the -NH arylamide group is a p-nitroaniline group or 7-amino-4-methylcoumarin.

[0099] In some embodiments, the C-terminus is modified with an ester group.

[0100] In some embodiments, the C-terminus is not modified.

[0101] In some embodiments, R 1 It does not exist, and R 2 It is D-aspartic acid.

[0102] In some embodiments, X 1 X 2 and X 3 It does not exist.

[0103] In some embodiments, R 4 It is D-Nal(2').

[0104] In some embodiments, Y 3 To Y 8 It does not exist.

[0105] In some embodiments, Y 1 It is D-valine and Y 2 It is D-proline; or Y-proline. 1 It is D-proline and Y 2 It is D-valine.

[0106] In some embodiments, Y 3 Existence and Y 4 To Y 8 It does not exist.

[0107] In some embodiments, Y1 is D-valine or D-proline; Y2 is D-valine or D-proline; and / or Y3 is D-valine or D-proline.

[0108] In some embodiments, Y 1 For D-valine, Y 2 It is D-valine and Y 3 For D-proline; Y 1For D-proline, Y 2 It is D-valine and Y 3 It is D-valine; Y 1 For D-valine, Y 2 It is D-proline and Y 3 It is D-valine; or Y-valine. 1 For D-proline, Y 2 It is D-valine and Y 3 It is D-proline.

[0109] In some embodiments, Y 3 and Y 4 It exists, and Y 5 To Y 8 It does not exist.

[0110] In some embodiments, Y 1 It is D-valine or D-proline; Y 2 It is D-valine or D-proline; Y 3 It is D-valine or D-proline; and / or Y 4 It is either D-valine or D-proline.

[0111] In some embodiments, Y 1 For D-valine, Y 2 For D-valine, Y 3 It is D-valine and Y 4 For D-proline; Y 1 For D-proline, Y 2 For D-valine, Y 3 It is D-valine and Y 4 It is D-valine; Y 1 For D-valine, Y 2 For D-proline, Y 3 It is D-valine and Y 4 It is D-valine; Y 1 For D-valine, Y 2 For D-valine, Y 3 It is D-proline and Y 4 It is D-valine; or Y-valine. 1 For D-valine, Y 2 For D-proline, Y 3 It is D-valine and Y 4 It is D-proline.

[0112] In some embodiments, R 1 R 2 and R 7 Existence and R 8 To R 20It does not exist, and the sequence of equation (I) passes through R. 2 and R 7 Cyclation via lactam bonds.

[0113] In some embodiments, R 1 R 2 R 7 and R 8 Existence and R 9 To R 20 It does not exist, and the sequence of equation (I) passes through R. 2 and R 8 Cyclation via lactam bonds.

[0114] In some embodiments, R 1 It is acetylated leucine;

[0115] R 2 It is aspartic acid;

[0116] R 3 Choose the group consisting of the following: proline, hydroxyproline, D-hydroxyproline, phenylalanine, and histidine;

[0117] R 4 For histidine or dNal(2');

[0118] R 5 For dNal(2') or arginine;

[0119] R 6 Choose the group consisting of the following: arginine, D-tryptophan, and L-tryptophan;

[0120] R 7 It is tryptophan or proline;

[0121] R 8 It is lysine;

[0122] Y 1 Choose from the group consisting of: D-valine, D-leucine, and D-isoleucine; and / or

[0123] Y 2 It is D-proline.

[0124] In some embodiments, the sequence of equation (I) is linear.

[0125] In some embodiments, the non-natural melanocortin analogue is present in the composition.

[0126] In some embodiments, the composition further comprises a pharmaceutical salt.

[0127] In some embodiments, the composition further comprises a pharmaceutical carrier.

[0128] In some embodiments, the non-naturally occurring melanocortin analogue is present in the composition at a concentration of 0.1 mg / mL to 500 mg / mL relative to the total volume of the composition.

[0129] In some embodiments, the non-naturally occurring melanocortin analogue is present in the composition at a concentration of about 50 mg / mL relative to the total volume of the composition.

[0130] In some embodiments, the non-natural melanocorticoid analogue is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intravenous, intranasal, or oral administration.

[0131] In some embodiments, the composition comprising the non-naturally occurring melanocorticoid analogue is administered parenterally to the subject.

[0132] In some embodiments, the composition comprising the non-naturally occurring melanocorticoid analogue is administered subcutaneously to the subject.

[0133] In some embodiments, the non-natural melanocortin analog crosses the subject's blood-brain barrier.

[0134] In some embodiments, the therapeutically effective dose of the non-naturally occurring melanocortin analogue is from 0.001 mg / kg to 25 mg / kg, depending on the subject's weight.

[0135] In some embodiments, the therapeutically effective dose of the non-naturally occurring melanocortin analogue is 0.5 mg / kg to 10 mg / kg, depending on the subject's weight.

[0136] In some embodiments, the non-natural melanocorticoid analogue is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg, depending on the subject's weight.

[0137] In some embodiments, the non-natural melanocorticoid analogue is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg, depending on the subject's weight.

[0138] In some embodiments, the non-natural melanocortin analogue is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

[0139] In some embodiments, the non-natural melanocortin analogue is administered to the subject for 1, 5, 7, 14, 21, 28, 35, 40, 45, 50, 60, 75, 90, 100, 110, or 120 days.

[0140] In some embodiments, the pharmaceutical carrier comprises water.

[0141] In some embodiments, the kidney disease and / or the liver disease is a fibrotic disease, optionally wherein the fibrotic kidney disease further includes fibrosis of at least a portion of the subject's kidney, and optionally wherein the fibrotic liver disease further includes fibrosis of at least a portion of the subject's liver.

[0142] In some embodiments, the kidney disease is chronic kidney disease (CKD) and / or kidney failure.

[0143] In some embodiments, the subject has undergone or is undergoing dialysis.

[0144] In some embodiments, the liver disease is non-alcoholic fatty liver disease (NAFLD).

[0145] In some embodiments, NAFLD stands for non-alcoholic steatohepatitis (NASH).

[0146] In some embodiments, prior to administration of the non-natural melanocorticoid analogue, the subject experienced loss of appetite, decreased appetite, reduced food consumption, and / or weight loss.

[0147] In some embodiments, the loss of appetite, decreased appetite, reduced food consumption, and / or weight loss are caused by the kidney disease and / or the liver disease.

[0148] In some embodiments, the loss of appetite, decreased appetite, reduced food consumption, and / or weight loss are caused by cachexia.

[0149] In some embodiments, the method or use (i) stimulates the subject's appetite; (ii) increases the subject's food consumption; (iii) prevents or alleviates the subject's nausea, vomiting, and / or anorexia; (iv) increases or maintains the subject's weight; (v) prevents or reduces the subject's weight loss; (vi) increases or maintains the subject's muscle mass; (vii) prevents or reduces the subject's muscle mass loss; (viii) increases or maintains the subject's fat mass; and / or (ix) prevents or reduces the subject's fat mass loss.

[0150] In some embodiments, the method or use increases the subject's weight and / or increases the subject's food consumption.

[0151] In some embodiments, after administration of the non-natural melanocortin analogue, the subject’s appetite increased by at least 10% to 200%.

[0152] In some embodiments, after administration of the non-natural melanocortin analogue, the subject’s appetite increased by at least 25% to 100%.

[0153] In some embodiments, during the administration of the non-naturally occurring melanocortin analogue, appetite increases for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

[0154] In some embodiments, the period of application of the non-naturally occurring melanocortin analogue is 1 day, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

[0155] In some embodiments, the increased appetite is sustained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

[0156] In some embodiments, the appetite is assessed using a scale for measuring food cravings, hunger, and / or satiety levels.

[0157] In some embodiments, the appetite is assessed between meals.

[0158] In some embodiments, the subject includes two or more subjects, and the appetite is the average appetite of the two or more subjects.

[0159] In some embodiments, after administration of the non-natural melanocortin analogue, the subject’s food consumption increased by at least 25% to 2,000%.

[0160] In some embodiments, after administration of the non-natural melanocortin analogue, the subject’s food consumption increased by at least 50% to 500%.

[0161] In some embodiments, during the administration of the non-naturally occurring melanocortin analogue, the food consumption increases for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

[0162] In some embodiments, during the administration of the non-naturally occurring melanocortin analogue, the food consumption increases for at least 1, 5, 7, 14, 21, 28, 35, 40, 45, 50, 60, 75, 90, 100, 110, or 120 days.

[0163] In some embodiments, the increased food consumption is sustained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

[0164] In some embodiments, the food consumption is determined by the total calories (kcal) consumed in a day or the mass (grams or kilograms) of food consumed in a day.

[0165] In some embodiments, anorexia is determined by food consumption.

[0166] In some embodiments, after administration of the non-natural melanocorticoid analogue, the subject's body weight increased by at least 5% to 200%.

[0167] In some embodiments, after administration of the non-natural melanocortin analogue, the subject's body weight increased by at least 5% to 25%.

[0168] In some embodiments, after administration of the non-natural melanocortin analogue, the subject's body weight increased by at least 20% to 100%.

[0169] In some embodiments, the weight gain is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years after the application of the non-natural melanocorticoid analogue is discontinued.

[0170] In some embodiments, after administration of the non-natural melanocortin analogue, the subject’s muscle mass increased by at least 1% to 100%.

[0171] In some embodiments, after administration of the non-natural melanocortin analogue, the subject's muscle mass increased by at least 5% to 15%.

[0172] In some embodiments, after administration of the non-natural melanocortin analogue, the subject's muscle mass increased by at least 25% to 50%.

[0173] In some embodiments, the increased muscle mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years after the application of the non-naturally occurring melanocortin analogue is discontinued.

[0174] In some embodiments, the muscle mass is cardiac muscle mass, skeletal muscle mass, or both.

[0175] In some embodiments, after administration of the non-natural melanocortin analogue, the subject’s fat mass increased by at least 1% to 100%.

[0176] In some embodiments, after administration of the non-natural melanocortin analogue, the subject’s fat mass increased by at least 5% to 15%.

[0177] In some embodiments, after administration of the non-natural melanocortin analogue, the subject’s fat mass increased by at least 25% to 50%.

[0178] In some embodiments, the increased fat mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

[0179] In some embodiments, the method or use stimulates the appetite of a subject who has the kidney disease or liver disease, in a control subject who has not been given the non-natural melanocorticoid analogue.

[0180] In some embodiments, the control subjects experienced loss of appetite, decreased appetite, reduced food consumption, and / or weight loss.

[0181] In some embodiments, the loss of appetite, decreased appetite, reduced food consumption, and / or weight loss are caused by the kidney disease or the liver disease.

[0182] In some embodiments, the loss of appetite, decreased appetite, reduced food consumption, and / or weight loss are caused by cachexia.

[0183] In some embodiments, the subject is a human being.

[0184] In some embodiments, the subjects are animals.

[0185] In some embodiments, the subject’s body mass index (BMI) is between 18.5 kg / m2 and 35 kg / m2.

[0186] In some embodiments, the subject's BMI is less than 20 kg / m2.

[0187] In some embodiments, the subject's BMI is less than 18.5 kg / m2.

[0188] In some embodiments, an appetite regulator is administered to the subject.

[0189] In some embodiments, the subject did not experience adverse events after administration of the non-natural melanocortin analogue.

[0190] In some embodiments, the subject did not experience any adverse events attributable to the non-naturally occurring melanocortin analogue after administration.

[0191] In some embodiments, the non-natural melanocortin analogue is administered to the subject after the subject has experienced the increase in appetite.

[0192] In some embodiments, the non-natural melanocortin analogue is administered to the subject after the subject has experienced the increase in food consumption.

[0193] In some embodiments, the non-natural melanocortin analogue is administered to the subject after the subject has experienced the weight gain.

[0194] In some embodiments, the subject was cachectic prior to administration of the non-natural melanocorticoid analogue.

[0195] In some embodiments, the subject is cachectic if he / she meets the Fearon weight loss criteria.

[0196] In some embodiments, the Fearon weight loss criteria include (1) a weight loss of more than 5% within 6 months prior to administration, or (2) a weight loss of more than 2%, wherein the subject’s BMI is less than 20 kg / m2 or the subject has sarcopenia.

[0197] In some embodiments, the subject is no longer cachectic after administration of the non-natural melanocorticoid analogue.

[0198] In some embodiments, the subject no longer meets the Fearon weight loss criteria after administration of the non-natural melanocorticoid analogue.

[0199] In some embodiments, the non-natural melanocorticoid analogue is continued to be administered to the subject after the subject is no longer cachectic.

[0200] In some embodiments, the non-natural melanocorticoid analogue is administered to the subject even after the subject no longer meets the Fearon weight loss criteria.

[0201] In some embodiments, the subject is pretreated with the non-natural melanocortin analogue before becoming cachexia.

[0202] In some embodiments, the subject does not meet the Fearon weight loss criteria. Attached Figure Description

[0203] Figure 1A to 1YYEmbodiments of the present invention are illustrated, showing the percentage activation of the melanocortin 3 receptor (MC3R), as measured by cAMP levels, after stimulation with a non-naturally occurring melanocortin analogue. Exemplary non-naturally occurring melanocortin analogues include HS024 (TFA) (…). Figure 1A ;SEQ ID NO:525), E1( Figure 3B ;SEQ ID NO:15), E2 ( Figure 1C ;SEQ ID NO:16), E3 ( Figure 1D ;SEQ ID NO:17), E4 ( Figure 1E ;SEQ ID NO:18), E5 ( Figure 1F ;SEQID NO:19), E6 ( Figure 1G ;SEQ ID NO:20), E7 ( Figure 1H ;SEQ ID NO:21), E8 ( Figure 1I ;SEQ ID NO:22), E9 ( Figure 1J ;SEQ ID NO:23), E10 ( Figure 1K ;SEQ ID NO:24), E11 ( Figure 1L ;SEQ ID NO:25), E12 ( Figure 1M ;SEQ ID NO:26), E13 ( Figure 1N ;SEQ ID NO:27), E14 ( Figure 10 ;SEQ ID NO:28), E15 ( Figure 1P ;SEQ ID NO:29), E16 ( Figure 1Q ;SEQ ID NO:30), E17 ( Figure 1R ;SEQ ID NO:31), E18 ( Figure 1S ;SEQ ID NO:32), E19 ( Figure 1T ;SEQ ID NO:35), E20 ( Figure 1U ;SEQ ID NO:36), E21 ( Figure 1V ;SEQ ID NO:37), F1 ( Figure 1W ;SEQ ID NO:40), F2 ( Figure 1X ;SEQ ID NO:41), F3 ( Figure 1Y ;SEQ ID NO:42), F4 ( Figure 1Z ;SEQ ID NO:43), F5 ( Figure 1AA ;SEQ ID NO:44), F6 ( Figure 1BB ;SEQ ID NO:50), F7 ( Figure 1CC;SEQ ID NO:51), F8 ( Figure 1DD ;SEQ ID NO:52), F9 ( Figure 1EE ;SEQ ID NO:53), F10 ( Figure 1FF ;SEQ ID NO:54), F11 ( Figure 1GG ;SEQ ID NO:55), F12 ( Figure 1HH ;SEQ ID NO:56), F13 ( Figure 1II ;SEQ ID NO:57), F14 ( Figure 1A JJ; SEQ ID NO:58), F15 ( Figure 1KK ;SEQ ID NO:59), F16 ( Figure 1LL ;SEQ ID NO:60), F17 ( Figure 1MM ;SEQID NO:61), F18 ( Figure 1NN ;SEQ ID NO:62), F19 ( Figure 100 ;SEQ ID NO:63), F20 ( Figure 1PP ;SEQ ID NO:64), F21 ( Figure 1 QQ ;SEQ ID NO:65), F22 ( Figure 1RR ;SEQ ID NO:45), F23 ( Figure 1SS ;SEQ ID NO:46), F24 ( Figure 1TT ;SEQ ID NO:47), F25 ( Figure 1UU ;SEQ ID NO:48), F26 ( Figure 1VV ;SEQ ID NO:49), F28 ( Figure 1WW ;SEQ ID NO:67), F29 ( Figure 1XX ; SEQ ID NO:68) and F30 (Fig. 30YY; SEQ ID NO:69).

[0204] Figures 2A to 200 Embodiments of the present invention are illustrated, showing the percentage of MC3R activation, as measured by cAMP levels, after stimulation with a non-naturally occurring melanocortin analogue. Exemplary non-naturally occurring melanocortin analogues include G5 (…). Figure 2A ;SEQ ID NO:77), G6 ( Figure 2B ;SEQ ID NO:78), G7 ( Figure 2C ;SEQ ID NO:75), G8 ( Figure 2D ;SEQ ID NO:74), G9 ( Figure 2E ;SEQ ID NO:79), G10 ( Figure 2F ;SEQ ID NO:80)、G11( Figure 2G ;SEQ ID NO:81)、G12( Figure 2H ;SEQ ID NO:82)、G13( Figure 2I ;SEQ ID NO:83)、G15( Figure 2J ;SEQ ID NO:85)、G17( Figure 2K ;SEQ ID NO:211)、G18( Figure 2L ;SEQ IDNO:212)、G19( Figure 2M ;SEQ ID NO:213)、G 20( Figure 2N ;SEQ ID NO:214)、H1( Figure 2O ;SEQ ID NO:97)、H2( Figure 2P ;SEQ ID NO:98)、H3( Figure 2Q ;SEQ ID NO:99)、H4( Figure 2R ;SEQ ID NO:100)、H5( Figure 2S ;SEQ ID NO:101)、H6( Figure 2T ;SEQ ID NO:102)、H7( Figure 2U ;SEQ ID NO:103)、H8( Figure 2V ;SEQID NO:104)、H9( Figure 2W ;SEQ ID NO:105)、H10( Figure 2X ;SEQ ID NO:106)、H11( Figure 2Y ;SEQ ID NO:107)、H12( Figure 2Z ;SEQ ID NO:108)、H13( Figure 2AA ;SEQ ID NO:109)、H14( Figure 2BB ;SEQ ID NO:110)、H15( Figure 2CC ;SEQ ID NO:111)、I1( Figure 2DD ;SEQ ID NO:112)、I2( Figure 2EE ;SEQ ID NO:113)、I3( Figure 2FF ;SEQ ID NO:119)、I4( Figure 2GG ;SEQ ID NO:115)、I5( Figure 2HH ;SEQ ID NO:120)、I6( Figure 2II ;SEQ ID NO:121)、I7( Figure 2JJ ;SEQ ID NO:116)、I8( Figure 2KK ;SEQ ID NO:117), I9 ( Figure 2LL ;SEQ ID NO:122), I10 ( Figure 2MM ;SEQ ID NO:123), I11( Figure 2NN ;SEQ ID NO:118) and I12 ( Figure 200 (SEQ ID NO:124).

[0205] Figures 3A to 3ZZ Embodiments of the present invention are illustrated, showing the percentage inhibition of MC3R, as measured by cAMP levels, after stimulation with a non-naturally occurring melanocortin analogue. Exemplary non-naturally occurring melanocortin analogues include J1 ( Figure 3A ;SEQ ID NO:126), J4 ( Figure 3B ;SEQ ID NO:129), J5 ( Figure 3C ;SEQ ID NO:130), J6 ( Figure 3D ;SEQ ID NO:131), J7 ( Figure 3E ;SEQ ID NO:132), J8 ( Figure 3F ;SEQ ID NO:133), J9 ( Figure 3G ;SEQ ID NO:134), J10 ( Figure 3H ;SEQ ID NO:135), J11 ( Figure 3I ; SEQ ID NO:136), J12 ( Figure 3J ;SEQ ID NO:137), J13 ( Figure 3K ; SEQ ID NO:138), J14 ( Figure 3L ;SEQ ID NO:139), J15 ( Figure 3M ;SEQ ID NO:140), J16 ( Figure 3N ;SEQ ID NO:141), J17 ( Figure 3O ;SEQ ID NO:142), J18 ( Figure 3P ;SEQ ID NO:143), J19 ( Figure 3Q ;SEQ ID NO:144), J20 ( Figure 3R ;SEQ ID NO:145), J21 ( Figure 3S ;SEQ ID NO:146), J22 ( Figure 3T ;SEQ ID NO:147), J23 ( Figure 3U ;SEQ ID NO:148), J24 ( Figure 3V; SEQ ID NO:149), J25( Figure 3W ; SEQ ID NO:150), J26( Figure 3X ; SEQ ID NO:151), J27( Figure 3Y ; SEQ ID NO:152), J28( Figure 3Z ; SEQ ID NO:153), J29( Figure 3AA ; SEQ ID NO:154), J30( Figure 3BB ; SEQ ID NO:155), J31( Figure 3CC ; SEQ ID NO:156), J32( Figure 3DD ; SEQ ID NO:157), J33( Figure 3EE ; SEQ ID NO:158), J34( Figure 3FF ; SEQ ID NO:159), J35( Figure 3GG ; SEQ ID NO:160), J36( Figure 3HH ; SEQ ID NO:161), J37( Figure 3II ; SEQ ID NO:126; SEQ ID NO:162), J38( Figure 3JJ ; SEQ IDNO:163), J39( Figure 3KK ; SEQ ID NO:164), J40( Figure 3LL ; SEQ ID NO:165), J41( Figure 3MM ; SEQ IDNO:166), J42( Figure 3NN ; SEQ ID NO:167), J43( Figure 300 ; SEQ ID NO:168), J44( Figure 3PP ; SEQ IDNO:169), J45( Figure 3 QQ ; SEQ ID NO:170), J46( Figure 3RR ; SEQ ID NO:171), J47( Figure 3SS ; SEQ IDNO:172), J48( Figure 3TT ; SEQ ID NO:173), J49( Figure 3UU ; SEQ ID NO:174), J60( Figure 3VV ; SEQ IDNO:185), J63( Figure 3WW ; SEQ ID NO:188), J65( Figure 3XX ; SEQ ID NO:190), J68( Figure 3YY ; SEQ IDNO:193) and J69( Figure 3ZZ(SEQ ID NO:194).

[0206] Figures 4A to 4SS Embodiments of the present invention are illustrated, showing the percentage inhibition of MC3R, as measured by cAMP levels, after stimulation with a non-naturally occurring melanocortin analogue. Exemplary non-naturally occurring melanocortin analogues include K2 (…). Figure 4A ;SEQ ID NO:394), K3 ( Figure 4B ;SEQ ID NO:396), K4 ( Figure 4C ;SEQ ID NO:398), K5 ( Figure 4D ;SEQ ID NO:399), K6 ( Figure 4E ;SEQ ID NO:392), K7 ( Figure 4F ;SEQ ID NO:393), K8 ( Figure 4G ;SEQ ID NO:395), K9 ( Figure 4H ;SEQ ID NO:397), K10 ( Figure 4I ;SEQ ID NO:400), K13 ( Figure 4J ;SEQ ID NO:403), K16 ( Figure 4K ;SEQ ID NO:376), K17 ( Figure 4L ;SEQ ID NO:377), K18 ( Figure 4M ;SEQ ID NO:378), K20 ( Figure 4N ;SEQ ID NO:380), K23 ( Figure 4O ;SEQID NO:388), L4 ( Figure 4P ;SEQ ID NO:217), M1 ( Figure 4Q ;SEQ ID NO:225), M2 ( Figure 4R ;SEQ ID NO:234), M3 ( Figure 4S ; SEQ ID NO:226), M4 ( Figure 4T ;SEQ ID NO:235), M5 ( Figure 4U ;SEQ ID NO:227), M6 ( Figure 4V ;SEQ ID NO:228), M7 ( Figure 4W ;SEQ ID NO:229), M8 ( Figure 4X ;SEQ ID NO:230), M9 ( Figure 4Y ;SEQ ID NO:231), M11 ( Figure 4Z; SEQ ID NO:233), N1 (Figure AA; SEQ ID NO:236), N2 ( Figure 4BB ;SEQ ID NO:237), N3 ( Figure 4CC ;SEQ ID NO:240), N4 ( Figure 4DD ;SEQ ID NO:241), N5 ( Figure 4EE ;SEQ ID NO:242), N6 ( Figure 4FF ;SEQ ID NO:243), N7 ( Figure 4GG ;SEQ ID NO:244), N8 ( Figure 4HH ;SEQ ID NO:245), O1( Figure 4II ;SEQ ID NO:246), O2 ( Figure 4JJ ;SEQ ID NO:247), O3 ( Figure 4KK ;SEQ ID NO:248), O4 ( Figure 4LL ;SEQ ID NO:249), O5 ( Figure 4MM ;SEQ ID NO:250), O6 ( Figure 4NN ;SEQ ID NO:255), O7 ( Figure 400 ;SEQ ID NO:256), O9 ( Figure 4PP ;SEQ ID NO:258), O10 ( Figure 4 QQ ;SEQ ID NO:259), O11( Figure 4RR ;SEQ ID NO:260) and TCMCB07 ( Figure 4SS ;SEQ ID NO:3).

[0207] Figures 5A to 5DD Embodiments of the present invention are illustrated showing the percentage activation of the melanocortin 4 receptor (MC4R), as measured by cAMP levels, after stimulation with a non-naturally occurring melanocortin analogue. Exemplary non-naturally occurring melanocortin analogues include HS024 (TFA) (…). Figure 5A ;SEQ ID NO:525), E1( Figure 5B ;SEQ ID NO:15), E2 ( Figure 5C ;SEQ ID NO:16), E3 ( Figure 5D ;SEQ ID NO:17), E4 ( Figure 5E ;SEQ ID NO:18), E5 ( Figure 5F ;SEQID NO:19), E6 ( Figure 5G ;SEQ ID NO:20), E7 ( Figure 5H ;SEQ ID NO:21), E8 ( Figure 5I ;SEQ ID NO:22)、E9( Figure 5J ;SEQ ID NO:23)、E10( Figure 5K ;SEQ ID NO:24)、E11( Figure 5L ;SEQ ID NO:25)、E12( Figure 5M ;SEQ ID NO:26)、E13( Figure 5N ;SEQ ID NO:27)、E14( Figure 5O ;SEQ ID NO:28)、E15( Figure 5P ;SEQ IDNO:29)、E16( Figure 5Q ;SEQ ID NO:30)、E17( Figure 5R ;SEQ ID NO:31)、E18( Figure 5S ;SEQ ID NO:32)、E20( Figure 5T ;SEQ ID NO:36)、E21( Figure 5U ;SEQ ID NO:37)、E22( Figure 5V ;SEQ ID NO:195)、E23( Figure 5W ;SEQ ID NO:196)、E24( Figure 5X ;SEQ ID NO:197)、F1( Figure 5Y ;SEQ ID NO:40)、F2( Figure 5Z ;SEQID NO:41)、F3( Figure 5AA ;SEQ ID NO:42)、F4( Figure 5BB ;SEQ ID NO:43)、F5( Figure 5CC ;SEQ ID NO:44)、F6( Figure 5DD ;SEQ ID NO:50)、F7( Figure 5EE ;SEQ ID NO:51)、F8( Figure 5FF ;SEQ ID NO:52)、F9( Figure 5GG ;SEQ ID NO:53)、F10( Figure 5HH ;SEQ ID NO:54)、F11( Figure 5II ;SEQ ID NO:55)、F12( Figure 5JJ ;SEQ ID NO:56)、F13( Figure 5KK ;SEQ ID NO:57)、F14( Figure 5LL ;SEQ ID NO:58)、F15( Figure 5MM ;SEQ ID NO:59)、F16( Figure 5NN;SEQ ID NO:60), F17 ( Figure 500 ;SEQ ID NO:61), F18 ( Figure 5PP ;SEQ ID NO:62), F19 ( Figure 5 QQ ;SEQ ID NO:63), F20 ( Figure 5RR ;SEQ ID NO:64), F21 ( Figure 5SS ;SEQ ID NO:65), F22 ( Figure 5TT ;SEQ ID NO:45), F23 ( Figure 5UU ;SEQ ID NO:46), F24 ( Figure 5VV ;SEQ ID NO:47), F25 ( Figure 5WW ;SEQ ID NO:48), F26 ( Figure 5XX ;SEQ ID NO:49), F27 ( Figure 5YY ;SEQ ID NO:66), F28 ( Figure 5ZZ ;SEQ ID NO:67), F29 ( Figure 5AAA ;SEQ ID NO:68), F30 ( Figure 5BBB ;SEQ ID NO:69), F31 ( Figure 5 CCC ;SEQ ID NO:201) and F32 ( Figure 5DDD (SEQ ID NO:205).

[0208] Figures 6A to 6ZZ Embodiments of the present invention are illustrated, showing the percentage activation of MC4R, as measured by cAMP levels, after stimulation with a non-naturally occurring melanocortin analogue. Exemplary non-naturally occurring melanocortin analogues include G1 (… Figure 6A ;SEQ ID NO:71), G2 ( Figure 6B ;SEQ ID NO:72), G3 ( Figure 6C ;SEQ ID NO:73), G4 ( Figure 6D ;SEQ ID NO:76), G5 ( Figure 6E ;SEQ ID NO:77), G6 ( Figure 6F ;SEQ ID NO:78), G7 ( Figure 6G ;SEQ ID NO:75), G8 ( Figure 6H ;SEQ ID NO:74), G9 ( Figure 6I ;SEQ ID NO:79), G10 ( Figure 6J ;SEQ ID NO:80), G11 ( Figure 6K ;SEQ ID NO:81), G12 ( Figure 6L;SEQ ID NO:82)、G13( Figure 6M ;SEQ ID NO:83)、G14( Figure 6N ;SEQ ID NO:84)、G15( Figure 6O ;SEQ ID NO:85)、G16( Figure 6P ;SEQ ID NO:86)、G17( Figure 6Q ;SEQ IDNO:211)、G18( Figure 6R ;SEQ ID NO:212)、G19( Figure 6S ;SEQ ID NO:213)、G20( Figure 6T ;SEQ ID NO:214)、G21( Figure 6U ;SEQ ID NO:215)、G22( Figure 6V ;SEQ ID NO:202)、G23( Figure 6W ;SEQ ID NO:203)、G24( Figure 6X ;SEQ ID NO:204)、H1( Figure 6Y ;SEQ ID NO:97)、H2( Figure 6Z ;SEQ ID NO:98)、H3( Figure 6AA ;SEQ ID NO:99)、H4( Figure 6BB ;SEQ ID NO:100)、H5( Figure 6CC ;SEQ ID NO:101)、H6( Figure 6DD ;SEQ IDNO:102)、H7( Figure 6EE ;SEQ ID NO:103)、H8( Figure 6FF ;SEQ ID NO:104)、H9( Figure 6GG ;SEQ ID NO:105)、H10( Figure 6HH ;SEQ ID NO:106)、H11( Figure 6II ;SEQ ID NO:107)、H12( Figure 6JJ ;SEQ ID NO:108)、H13( Figure 6KK ;SEQ ID NO:109)、H14( Figure 6LL ;SEQ ID NO:110)、H15( Figure 6MM ;SEQ ID NO:111)、I1( Figure 6NN ;SEQ ID NO:112)、I2( Figure 600 ;SEQ ID NO:113)、I3( Figure 6PP ;SEQ ID NO:119)、I4( Figure 6 QQ;SEQ ID NO:115), I5 ( Figure 6RR ;SEQ ID NO:120), I6 ( Figure 6SS ;SEQ ID NO:121), I7 ( Figure 6TT ;SEQ ID NO:116), I8 ( Figure 6UU ;SEQ ID NO:117), I9 ( Figure 6VV ;SEQ ID NO:122), I10 ( Figure 6WW ;SEQ ID NO:123), I11( Figure 6XX ;SEQ ID NO:118), I12 ( Figure 6YY ;SEQ ID NO:124) and I13 ( Figure 6ZZ (SEQ ID NO:200).

[0209] Figures 7A to 7RRR Embodiments of the present invention are illustrated, showing the percentage inhibition of MC4R, as measured by cAMP levels, after stimulation with a non-naturally occurring melanocortin analogue. Exemplary non-naturally occurring melanocortin analogues include J1 ( Figure 7A ;SEQ ID NO:126), J2( Figure 7B ;SEQ ID NO:127), J3 ( Figure 7C ;SEQ ID NO:128), J4 ( Figure 7D ;SEQ ID NO:129), J5 ( Figure 7E ;SEQ ID NO:130), J6 ( Figure 7F ;SEQ ID NO:131), J7 ( Figure 7G ;SEQ ID NO:132), J8 ( Figure 7H ;SEQ ID NO:133), J9 ( Figure 7I ;SEQ ID NO:17), J10 ( Figure 7J ;SEQ ID NO:135), J11 ( Figure 7K ; SEQ ID NO:136), J12 ( Figure 7L ;SEQ ID NO:137), J13 ( Figure 7M ; SEQ ID NO:138), J14 ( Figure 7N ;SEQ ID NO:139), J15 ( Figure 7O ;SEQ ID NO:140), J16 ( Figure 7P ;SEQ ID NO:141), J17 ( Figure 7Q ;SEQ ID NO:142), J18 ( Figure 7R;SEQ ID NO:143)、J19( Figure 7S ;SEQ ID NO:144)、J20( Figure 7T ;SEQ ID NO:145)、J21( Figure 7U ;SEQ ID NO:146)、J22( Figure 7V ;SEQ ID NO:147)、J23( Figure 7W ;SEQ ID NO:148)、J24( Figure 7X ;SEQ ID NO:149)、J25( Figure 7Y ;SEQ ID NO:150)、J26( Figure 7Z ;SEQ ID NO:151)、J27( Figure 7AA ;SEQ ID NO:152)、J28( Figure 7BB ;SEQ ID NO:153)、J29( Figure 7CC ;SEQ ID NO:154)、J30( Figure 7DD ;SEQ ID NO:155)、J31( Figure 7EE ;SEQ ID NO:156)、J32( Figure 7FF ;SEQ ID NO:157)、J33( Figure 7GG ;SEQ ID NO:158)、J34( Figure 7HH ;SEQ ID NO:159)、J35( Figure 7II ;SEQ ID NO:160)、J36( Figure 7JJ ;SEQ ID NO:161)、J37( Figure 7KK ;SEQ ID NO:126;SEQ ID NO:162)、J38( Figure 7LL ;SEQ ID NO:163)、J39( Figure 7MM ;SEQ ID NO:164)、J40( Figure 7NN ;SEQ IDNO:165)、J41( Figure 700 ;SEQ ID NO:166)、J42( Figure 7PP ;SEQ ID NO:167)、J43( Figure 7 QQ ;SEQ ID NO:168)、J44( Figure 7RR ;SEQ ID NO:169)、J45( Figure 7SS ;SEQ ID NO:170)、J46( Figure 7TT ;SEQ ID NO:171)、J47( Figure 7UU ;SEQ ID NO:172)、J48( Figure 7VV;SEQ ID NO:173), J49 ( Figure 7WW ;SEQ ID NO:174), J50 ( Figure 7XX ;SEQ ID NO:175), J51 ( Figure 7YY ;SEQ ID NO:176), J52 ( Figure 7ZZ ;SEQ ID NO:177), J53 ( Figure 7AAA ;SEQ ID NO:178), J54 ( Figure 7BBB ;SEQ ID NO:179), J55 ( Figure 7 CCC ;SEQ ID NO:180), J56 ( Figure 7DDD ;SEQ ID NO:181), J57 ( Figure 7 EEE ;SEQ ID NO:182), J58 ( Figure 7FFF ;SEQ ID NO:183), J59 ( Figure 7GGG ;SEQ ID NO:184), J60 ( Figure 7HHH ;SEQ ID NO:185), J61 ( Figure 7III ;SEQ ID NO:186), J62 ( Figure 7 JJJ ; SEQ ID NO:187), J63 ( Figure 7KKK ;SEQ ID NO:188), J64 ( Figure 7LLL ;SEQ ID NO:189), J65 ( Figure 7MMM ; SEQ ID NO:190), J66 ( Figure 7 NNN ;SEQ ID NO:191), J67 ( Figure 7000 ;SEQ ID NO:192), J68 ( Figure 7 PPP ; SEQ ID NO:193), J69 ( Figure 7 QQ ;SEQ ID NO:194) and J70 ( Figure 7 RRR (SEQ ID NO:206).

[0210] Figures 8A to 8GGG Embodiments of the present invention are illustrated, showing the percentage inhibition of MC4R, as measured by cAMP levels, after stimulation with a non-naturally occurring melanocortin analogue. Exemplary non-naturally occurring melanocortin analogues include K1 (…). Figure 8A ;SEQ ID NO:391), K2 ( Figure 8B ;SEQ ID NO:394), K3 ( Figure 8C ;SEQ ID NO:396), K4 ( Figure 8D ;SEQ ID NO:398), K5 ( Figure 8E ;SEQ ID NO:399)、K6( Figure 8F ;SEQ ID NO:392)、K7( Figure 8G ;SEQ ID NO:393)、K8( Figure 8H ;SEQ ID NO:395)、K9( Figure 8I ;SEQ ID NO:397)、K10( Figure 8J ;SEQ ID NO:400)、K11( Figure 8K ;SEQ ID NO:401)、K12( Figure 8L ;SEQID NO:402)、K13( Figure 8M ;SEQ ID NO:403)、K14( Figure 8N ;SEQ ID NO:406)、K15( Figure 8O ;SEQ IDNO:375)、K16( Figure 8P ;SEQ ID NO:376)、K17( Figure 8Q ;SEQ ID NO:377)、K18( Figure 8R ;SEQ ID NO:378)、K19( Figure 8S ;SEQ ID NO:379)、K20( Figure 8T ;SEQ ID NO:380)、K21( Figure 8U ;SEQ ID NO:381)、K22( Figure 8V ;SEQ ID NO:125)、K23( Figure 8W ;SEQ ID NO:388)、L1( Figure 8X ;SEQ ID NO:198)、L2( Figure 8Y ;SEQ ID NO:199)、L3( Figure 8Z ;SEQ ID NO:216)、L4( Figure 8AA ;SEQ ID NO:217)、L5( Figure 8BB ;SEQID NO:220)、M1( Figure 8CC ;SEQ ID NO:225)、M2( Figure 8DD ;SEQ ID NO:234)、M3( Figure 8EE ;SEQ IDNO:226)、M4( Figure 8FF ;SEQ ID NO:237)、M5( Figure 8GG ;SEQ ID NO:227)、M6( Figure 8HH ;SEQ ID NO:228)、M7( Figure 8II ;SEQ ID NO:229)、M8( Figure 8JJ ;SEQ ID NO:230), M9 ( Figure 8KK ;SEQ ID NO:231), M10 ( Figure 8LL ;SEQ ID NO:232), M11 ( Figure 8MM ;SEQ ID NO:233), N1 ( Figure 8NN ;SEQ ID NO:236), N2 ( Figure 800 ;SEQ ID NO:237), N3 ( Figure 8PP ;SEQ ID NO:239), N4 ( Figure 8 QQ ;SEQ ID NO:241), N5 ( Figure 8RR ;SEQ ID NO:242), N6 ( Figure 8SS ;SEQ ID NO:243), N7 ( Figure 8TT ;SEQ ID NO:244), N8 ( Figure 8UU ;SEQ ID NO:245), O1( Figure 8VV ;SEQ ID NO:246), O2 ( Figure 8WW ;SEQ ID NO:247), O3 ( Figure 8XX ;SEQ ID NO:248), O4 ( Figure 8YY ;SEQ ID NO:249), O5 ( Figure 8ZZ ;SEQ ID NO:250), O6 ( Figure 8AAA ;SEQ ID NO:255), O7 ( Figure 8BBB ;SEQ ID NO:256), O8 ( Figure 8 CCC ;SEQ ID NO:257), O9 ( Figure 8DDD ;SEQ ID NO:258), O10 ( Figure 8 EEE ;SEQ ID NO:259), O11( Figure 8FFF ;SEQ ID NO:260) and TCMCB07 ( Figure 8GGG ;SEQ ID NO:3).

[0211] Figures 9A to 9G Subcutaneous administration of TCMCB07 showed that it improved anorexia, weight loss, and lean body mass loss in rats with CKD-induced cachexia. Figure 9A This is a diagram depicting an in vivo model of renal failure (5 / 6 nephrectomy model) designed in rats using one or more compositions of the present invention. Figure 9B This is the basis for comparing the application of saline (Neph / saline) or TCMCB07 (Neph / TCMCB07) respectively. Figure 9AA graph showing the daily body weight of rats that underwent nephrectomy and sham-operated rats administered saline (Sham / saline) for 28 consecutive days in an in vivo model of renal failure. Figure 9C This is the basis for comparing the application of saline (Neph / saline) or TCMCB07 (Neph / TCMCB07) respectively. Figure 9A A graph showing the daily food intake over 28 days in rats that underwent nephrectomy and sham-operated rats administered saline (Sham / saline) in an in vivo model of renal failure. Figure 9D It describes the basis for applying saline (Neph / saline) or TCMCB07 (Neph / TCMCB07) respectively. Figure 9A A bar chart showing the increase in fat mass over 28 days in rats that underwent nephrectomy and sham-operated rats administered saline (Sham / saline). Figure 9E This is a graph showing the weight gain (%, net increase relative to baseline) after nephrectomy and treatment. Figure 9F It is a graph showing the cumulative food intake after treatment. Figure 9G This is a graph showing lean body mass determined by MR before treatment (day 14) and after treatment (day 28), and the increase (%) was calculated (net increase relative to baseline normalized). All data for each group are expressed as mean ± SEM. Two-way ANOVA in (9B to 9E), unpaired Student's t-test in (9D and 9G), * and #p < 0.05, ##p < 0.01, *** and ###p < 0.001, and ****p < 0.0001. Asterisks in (9B and 9C): Neph / saline group vs. Sham / saline group, and red hash marks in (9B and 9C): Neph / TCMCB07 group vs. Neph / saline group.

[0212] Figure 10A To F shows in Figure 9A In the CKD model of G, the effect of continuing TCMCB07 treatment after the rats reached the equivalence point was observed. The body weight of the rats treated with TCMCB07 was no different from that of the sham rats. Figure 10A A schematic diagram of the experimental method is shown. Figure 10B The daily body weight of CKD model rats treated with TCMCB07 and whose administration at the equivalent point changed is shown. Figure 10C The daily weight gain of CKD model rats treated with TCMCB07 and whose administration at the equivalent point resulted in changes compared to day 1 is shown. Figure 10D Weight gain is shown as a percentage of initial body weight in CKD model rats treated with TCMCB07 and whose changes occurred at the equivalent point, compared to day 1. Figure 10EWeight gain is shown as a percentage of initial body weight in CKD model rats treated with TCMCB07 and whose changes occurred at the point of equivalence, compared to day 14. Figure 10F The cumulative food intake of CKD model rats treated with TCMCB07 and altered at the point of equivalent administration is shown.

[0213] Figures 11A to 11F This illustrates the changes observed when treated with TCMCB07 and administered at the equivalent point. Figure 12A Body composition of CKD model rats up to 12G. Figure 11A The fat mass was shown; Figure 11B Lean body mass was shown; Figure 11C The fluid mass is shown; Figure 11D It shows increased fat mass; Figure 11E The increased lean body mass was shown; and Figure 11F The increased fluid mass is shown.

[0214] Figures 12A to 12D This illustrates the changes observed when treated with TCMCB07 and administered at the equivalent point. Figure 12A Tissue weight and length in CKD model rats up to 12G. Figure 12A The heart weight is shown; Figure 12B The weight of the gastrocnemius muscle is shown; Figure 12C The spleen weight was shown; and Figure 12D The body length is shown.

[0215] Figure 13A and 13B This illustrates the changes observed when treated with TCMCB07 and administered at the equivalent point. Figures 9A to 9G Serum creatinine and urea levels in CKD model rats. Figure 13A Serum creatinine was shown, and Figure 13B Serum blood urea nitrogen (BUN) is shown.

[0216] Figure 14 Showing from Figure 9A High-performance liquid chromatography (HPLC) chromatograms of plasma from CKD model rats to G. Time points were before intravenous administration and 2 minutes after administration of 750 nmol / kg TCMCB07. The plasma concentration of TCMCB07 was 7 nmol / mL 2 minutes after intravenous administration.

[0217] Figure 15 shows the data from... Figure 9AHigh-performance liquid chromatography (HPLC) chromatogram of cerebrospinal fluid (CSF) from CKD model rats to G. Time points: before administration, 5 min after intravenous TCMCB07 (750 nmol / kg), and 30 min after administration. The small peak at the 12.9 min retention time in the sample before administration represents the co-eluted fraction of CSF. The inset (top left) shows the CSF concentration of the proposed TCMCB07 metabolite increasing over time (expressed as peak height).

[0218] Figures 16A to 16C Mass spectrometry analysis of the eluent collected from the peak at a retention time of 12.9 min is shown. The arrows indicate the presence of peptides in the post-injection sample, but not in the pre-injection sample. The peak has an atomic weight of 1,209 Daltons, which is 21 Daltons less than that of cyclized TCMCB07 (1,230 Da). Detailed Implementation

[0219] The present invention includes a method for promoting appetite and / or increasing weight in a subject suffering from kidney disease and / or liver disease by administering a non-naturally occurring melanocortin analogue. In some embodiments, promoting appetite includes stimulating appetite. The non-naturally occurring melanocortin analogue may be present in the pharmaceutical composition and delivered via parenteral administration (e.g., subcutaneous injection). The appetite-promoting method may result in increased food consumption, weight gain, muscle mass, and / or fat mass in the subject. The method may also prevent or alleviate nausea, vomiting, and / or anorexia in the subject. The subject may have kidney disease, such as chronic kidney disease (CKD) and / or kidney failure (e.g., chronic renal failure). Alternatively or additionally, the subject may have liver disease, such as non-alcoholic fatty liver disease (NAFLD), such as non-alcoholic steatohepatitis (NASH). The kidney disease and / or liver disease may be fibrotic.

[0220] The method of this invention uses non-naturally occurring melanocortin receptor antagonist analogs, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, collectively referred to herein as melanocortin antagonists. Some melanocortin antagonists may bind only to melanocortin 3 or melanocortin 4 receptors. Other melanocortin antagonists may bind to melanocortin 3 receptors with a greater affinity than melanocortin 4 receptors, while other melanocortin antagonists may bind to melanocortin 4 receptors with a greater affinity than melanocortin 3 receptors. Certain melanocortin antagonists may bind to melanocortin 3 receptors with the same or generally similar affinity as melanocortin 4 receptors.

[0221] Each non-natural melanocortin analogue may possess one or more β-hairpin and / or β-turn structures. Rigidly structured amino acids (e.g., Aia, Aba, Ata, Hyp, D-Hyp, Pro, D-Pro, transPro(guan), and cisPro(guan)) may contribute to the formation of β-hairpin and / or β-turn structures in the peptide. Additionally, D-Met and disulfide bonds (via disulfide cyclization) can induce and / or stabilize the β-turn structure of non-natural melanocortin analogues. Pro-Gly and Gly-Gly linkers can also induce and / or stabilize β-turns. Generally, cyclization stabilizes β-turns, while D-amino acids can induce and / or stabilize β-turns. Non-natural melanocortin analogues include D-valine-D-proline (dV-dP) or D-proline-D-valine (dP-dV) as their C-terminus, which can provide enhanced transport and resistance to degradation. Non-natural melanocortin analogues can be linear or optionally cyclized at different positions on the peptide chain via disulfide bridges or lactam bonds. Each non-natural melanocortin analogue may contain one or more of the above features.

[0222] The following description is merely exemplary in nature and is not intended to limit the technology of the invention, its application, or its use. In all the drawings, corresponding reference numerals indicate the same or corresponding parts and features. The description of specific examples shown in various embodiments of the technology of the invention is for illustrative purposes only and is not intended to limit the scope of the technology of the invention. Furthermore, listing multiple embodiments having the described features does not imply the exclusion of other embodiments having additional features or other embodiments incorporating different combinations of the described features.

[0223] Furthermore, the detailed description of various embodiments herein is referenced to the accompanying drawings, which illustrate various embodiments by way of illustration. While the embodiments have been described in sufficient detail to enable those skilled in the art to practice the invention, other embodiments may be implemented, and logical and mechanical changes may be made, without departing from the spirit and scope of the invention. Therefore, the specific embodiments described herein are presented for illustrative purposes only and not for limitation. For example, the steps or functions, any methods, systems, or processes described in the specification may be performed in any order, and are not limited to the order shown. Furthermore, any step or function may be outsourced to or performed by one or more third parties.

[0224] definition

[0225] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. For the purposes of this invention, the following terms are defined.

[0226] The articles “a” and “a kind” in this text refer to one or more grammatical objects of the article (i.e., at least one). For example, “element” means one or more elements.

[0227] The term "about" means a quantity, level, value, number, frequency, percentage, size, volume, weight, or length that varies within a level acceptable in the art. In some embodiments, such variation can be up to 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a reference quantity, level, value, number, frequency, percentage, size, volume, weight, or length. When the term "about" is used in conjunction with a numerical range, the term modifies the range by extending the limits above and below the stated numerical value.

[0228] The term "administering" or "administer" includes the delivery of a non-naturally occurring melanocortin analogue (also referred to herein as a peptide) of the present invention to a subject by local or systemic administration. Administration can be local (including ocular and mucous membranes, including vaginal and rectal delivery), pulmonary (e.g., by inhalation or blowing of powder or aerosol, including via a nebulizer), intratracheal, intranasal, epidermal, and percutaneous, oral, or parenteral administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial (e.g., intrathecal or intraventricular) administration. Administration includes pre-administration of a non-naturally occurring melanocortin analogue prior to the onset of symptoms.

[0229] The terms “melanocortin analogue,” “non-naturally occurring melanocortin analogue,” “melanocortin peptide,” “melanocortin receptor peptide,” or “melanocortin” are used interchangeably and refer to melanocortin receptor ligands, which are large molecules containing at least one melanocortin pharmacophore. Melanocortin analogues are typically peptides that bind to melanocortin receptors under physiological conditions. Melanocortin analogues include naturally occurring and non-naturally occurring melanocortin analogues (i.e., “synthetic peptides” or “synthetic analogues”) as well as truncated and / or modified forms of full-length melanocortin proteins or peptides. For example, full-length POMC consists of 241 amino acids before proteolytic cleavage into “subpeptides.” Tissue-specific proteolytic cleavage of POMC produces peptides ranging in size from 13 to 76 amino acids. See Bicknell and Lawry, Encyclopedia of Stress, Vol. 3, pp. 257–265, Academic Press (2000). As discussed herein, synthetic, non-natural melanocortin analogs with increased melanocortin receptor activity are approximately 7 to 12 amino acids in size. Melanocortin analogs exhibit binding functionality to the melanocortin receptor. Binding to the melanocortin receptor is inhibitory (antagonistic). In addition to peptides, non-natural melanocortin analogs also include small molecule analogs of melanocortin or its components, consisting of organic compounds, inorganic compounds, or combinations of peptides and small molecules (i.e., peptide mimics), or various combinations thereof. “Non-natural melanocortin analogs” are structurally similar to and / or may be functionally similar to the biological melanocortin protein in their ability to bind to the melanocortin receptor. Furthermore, melanocortin analogs typically contain a pharmacophore: His-Phe-Arg-Trp (SEQ ID NO:1) or its modified form, or a structural or functional peptide mimic.

[0230] A pharmacophore is the smallest set of amino acid residues required to achieve a physiological effect; or, in the case of a receptor, a small molecule that mimics the structure of the amino acid residues required to bind to and activate the receptor. His-Phe-Arg-Trp (SEQ ID NO:1) and its analogues are pharmacophores of melanocortin used to regulate physiological effects. Therefore, non-natural melanocortin pharmacophore analogues can be small peptides or organic molecules designed to mimic the appearance or function (including activation or inactivation of receptor activity) of the core sequence peptide of the melanocortin pharmacophore.

[0231] "Enhanced therapeutic activity" refers to the increased melanocortin activity of non-natural melanocortin analogs derivatized at the N-terminus and / or C-terminus. Such derivatization does not necessarily involve a pharmacophore, but it does imply a relative increase in the biological half-life in vivo.

[0232] Melanocortin receptor "antagonists" are naturally occurring substances or manufactured pharmaceutical substances or compositions that can counteract melanocortin receptor-related responses that are typically induced by melanocortin receptor agonists.

[0233] The terms “bind,” “binding,” “complex,” and “complexing” refer to all types of physical and chemical bonding, reaction, compounding, attraction, chelation, etc.

[0234] The “peptide” as described herein may be (a) naturally occurring, (b) produced by chemical synthesis, (c) produced by recombinant DNA technology, (d) produced by biochemical or enzymatic fragmentation of a larger molecule, (e) produced by a combination of the methods listed above (a) to (d), or (f) produced by any other method for producing peptides.

[0235] As used herein, the term "peptide" includes any structure consisting of two or more amino acids, including chemical modifications and derivatives of amino acids. All or part of the amino acids forming a peptide can be naturally occurring amino acids, stereoisomers and modifications of such amino acids, non-protein amino acids, post-translational modified amino acids, enzymatically modified amino acids, constructs or structures designed to mimic amino acids, etc. Therefore, the term "peptide" includes pseudopeptides and peptide mimics, including structures with a non-peptide backbone. The term "peptide" also includes dimers or polymers of peptides. "Manufactured" peptides include peptides produced by chemical synthesis, recombinant DNA technology, biochemical or enzymatic fragmentation of larger molecules, combinations of the foregoing methods, or generally by any other method. The term "peptide" includes peptides containing a variable number of amino acid residues, optionally having non-amino acid residue groups at the N-terminus and C-terminus, such groups particularly including acyl, acetyl, alkenyl, alkyl, N-alkyl, amine, or amide groups.

[0236] By employing chemical synthesis (a useful production method), various amino acids not naturally present in the chain can be introduced, and the N-terminus or C-terminus can be modified, thereby providing improved stability and formulation, resistance to protease degradation, etc.

[0237] An "amino acid" is a molecule containing an amine group, a carboxylic acid group, and a side chain characteristic of each amino acid. The main elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen, and it has the general formula H₂N—CHR—COOH, where R represents a side chain group. Various α-amino acids differ in the side chain portion attached to the α-carbon. The "amino acid" in this invention includes known naturally occurring protein amino acids, referred to by their common three-letter and single-letter abbreviations. See, in general, Synthetic Peptides: A User's Guide, G.A. Grant, editor, W.H. Freeman & Co., New York (1992), whose teachings are incorporated herein by reference, including the text and tables shown on pages 11–24. As noted above, the term "amino acid" also includes naturally occurring protein amino acids, non-protein amino acids, post-translational modified amino acids, enzymatically synthesized amino acids, derived amino acids, stereoisomers and modifications designed to mimic the structure of amino acids, etc. Modified and uncommon amino acids are generally described in Synthetic Peptides: A User's Guide, ibid.; Hruby et al., Biochem. J. 268:249-262 (1990); and Toniolo, Int. J. Peptide Protein Res. 35:287-300 (1990); the teachings of all these references are incorporated herein by reference.

[0238] As used herein, the phrase "amino acid side chain moiety" (including as used in the specification and claims) includes any side chain of any amino acid, as the term "amino acid" is defined herein. Therefore, this includes side chain moiety present in naturally occurring amino acids. It further includes side chain moiety of modified naturally occurring amino acids, such as glycosylated amino acids. It further includes side chain moiety in the form of naturally occurring protein amino acids, non-protein amino acids, post-translational modified amino acids, enzymatically synthesized amino acids, derived amino acids, stereoisomers designed to mimic the structure of amino acids, etc., and modified side chain moiety. For example, side chain moiety of any amino acid of the present invention is included within the definition. "Derivatives" of amino acid side chain moiety are included within the definition of amino acid side chain moiety.

[0239] The term "derivative" of an amino acid side chain moiety includes any modification or variation of any amino acid side chain moiety, including modifications of naturally occurring amino acid side chain moieties. By way of example, derivatives of amino acid side chain moieties include straight-chain or branched, cyclic or acyclic, substituted or unsubstituted, saturated or unsaturated alkyl, aryl, or aralkyl moieties.

[0240] In the peptides described herein, the conventional amino acid residues have the conventional meanings given in section 2400 of the Manual of Patent Examining Procedure, 8th edition. Therefore, “Ala” is alanine; “Arg” is arginine; “Asn” is asparagine; “Asp” is aspartic acid; “Cys” is cysteine; “Gln” is glutamine; “Glu” is glutamic acid; “His” is histidine; “Ile” is isoleucine; “Leu” is leucine; “Lys” is lysine; “Met” is methionine; “Phe” is phenylalanine; “Pro” is proline; “Ser” is serine; “Thr” is threonine; “Trp” is tryptophan; “Tyr” is tyrosine; and “Val” is valine. Unless otherwise indicated, all amino acid abbreviations represent isomers, i.e., L-isomers, D-isomers, or combinations thereof may be used. Therefore, for example, "L-Phe" or "lPhe" is L-phenylalanine; "D-Phe" or "dPhe" is D-phenylalanine; dVal is D-valine; dPro is D-proline; "D- / L-Phe" or "d / lPhe" is D-phenylalanine, L-phenylalanine or a combination thereof; "Phe" can also be D-phenylalanine, L-phenylalanine or a combination thereof, etc. Non-standard amino acids: "Nle" is leucine; "Nal" is naphthylalanine; "D-Nal" is D-naphthylalanine; D-Nal(2') or DNal(2') is D-2'-naphthylalanine; L-Nal(2') or LNal(2') is L-2'-naphthylalanine; L-Nal(1') is L-1'-naphthylalanine; D-Nal(1') or DNal(1') is D-1'-naphthylalanine; Tle is tertiary leucine; Nva is valine; Orn is ornithine; Bip is biphenyl amino acid; etc.

[0241] α-amino acids have the general formula H2N—C α HR—COOH, where R is the side chain portion, and the amino group is attached to the carbon atom (i.e., the α-carbon) immediately adjacent to the carboxylic acid group. Other types of amino acids exist when the amino group is attached to different carbon atoms. For example, β-amino acids, where the carbon atom to which the amino group is attached is connected to the carboxylic acid group by a single carbon atom (C). β Separated. For example, α-alanine has the formula H2N—C α H(CH3)—COOH. In contrast, β-alanine has the general formula H2N—C. β H2—C α H2—COOH (i.e., 3-aminopropionic acid).

[0242] When β-amino acids are incorporated into peptides, there are two main types of β-peptides: those with a side chain residue R located on the carbon atom immediately adjacent to the amine are called β-peptides. 3 Peptides, and those with side chain residues on the carbon atom immediately adjacent to the carbonyl group, are called β-peptides. 2 Amino acids. As a non-limiting example, "β-valine" can refer to:

[0243] —NH—C β H2—C α H(CH3)2—CO—, i.e., β 2 -Valine (R on the carboxyl side);

[0244] —NH—C β H(CH3)2—C α H2—CO—, that is, β 3 -valine (R on the amino side); or

[0245] —NH—C β H(CH3)2—C α H(CH3)2—CO—, i.e., β 2,3 -Valine (R at two positions).

[0246] Furthermore, β-amino acids can have L- or D-stereochemistry. Unless otherwise indicated, all β-amino acid abbreviations represent isomers, namely L-isomers, D-isomers, or combinations thereof.

[0247] γ-amino acids are amino acids in which the carbon atom to which the amino group is attached is separated from the carboxylic acid moiety by two carbon atoms. For example, γ-aminobutyric acid has the formula H₂N—C. γ H2—C β H2—C α H2—COOH.

[0248] For information on other modified and less common amino acids, see §2422 of the MPEP, particularly Table 4 on pages 2400-24. Furthermore, “Ac” indicates an N-acetyl group, and “cyclic” indicates a cyclic structure, also referred to as “c” or “lactam” in the literature. “NH2” indicates an amine group, usually added to the C-terminus of the peptide. Therefore, as used herein, the –NH2 portion at the C-terminus of the peptide indicates an amidated C-terminus. Additionally, the following abbreviations are used herein: Harg for high-arginine; Hlys for high-lysine.

[0249] The following abbreviations are used: tBu for tert-butyl; Hyp(Bzl) for benzyl-L-hydroxy-proline; Mamb for 3-aminomethyl-benzoic acid; glutaric acid linker: CO—(CH2)3—CO; Pen for L-penicillamine; Aib for 2-aminoisobutyric acid; Aba for 4-amino-1,2,4,5-tetrahydro-2-benzozazepine-3-one; Pip for piperidine-2-carboxylic acid; Nip for piperidine-3-carboxylic acid; Tic for tetrahydroquinoline-3-carboxylic acid; Bip for biphenylalanine; Phg for α-phenyl-glycine; Sar for sarcosine; Azt for 3'-azido-3'-deoxythymidine; Oic for octahydroindole-2-carboxylic acid; Ata for 7-amino-7,8-dihydro4H-(1,2,3)triazole. (1,5-a)(1,4)diazazo-6(5H)-one; Aia is 4-amino-1,4,5,6-tetrahydrodiazazo-(4,3-b)indol-3(2H)-one; Mamb is 3-aminomethylbenzoic acid; Atc is 2-aminotetrahydronaphthyl-2-carboxylic acid; APC is 1-amino-4-phenylcyclohexane-carboxylic acid; APPC is 4-aminophenylpiperidine-4-carboxylic acid; Accc is 1-aminocyclo-propane-1-carboxylic acid; Aic is 2-aminoindanone-2-carboxylic acid; p(Cl)Phe is p-chloro-phenylalanine (I-iodine, Br-bromine, F-fluorine, CF3-trifluoromethyl); and p(Cl)dPhe is p-chloro-D-phenylalanine (I-iodine, Br-bromine, F-fluorine, CF3-trifluoromethyl).

[0250] The term "olefin" includes unsaturated hydrocarbons containing one or more carbon-carbon double bonds. Examples of such olefin groups include ethylene, propylene, etc.

[0251] The term "alkenyl" includes straight-chain monovalent hydrocarbon groups with two to six carbon atoms containing at least one double bond, or branched monovalent hydrocarbon groups with three to six carbon atoms; examples include vinyl, 2-propenyl, etc.

[0252] The term "alkyl" as used herein includes alkyl groups with a straight-chain or branched configuration of a specified length. Examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, etc.

[0253] The term "alkynyl" includes straight-chain monovalent hydrocarbon groups with two to six carbon atoms containing at least one triple bond, or branched monovalent hydrocarbon groups with three to six carbon atoms; examples include ethynyl, propynyl, butynyl, etc.

[0254] The term "aryl" includes a monovalent or bicyclic aromatic hydrocarbon group having 6 to 12 ring atoms, optionally substituted by one or more substituents selected from: alkyl, haloalkyl, cycloalkyl, alkoxy, alkylthio, halo, nitro, acyl, cyano, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxyl, or alkoxy-carbonyl. Examples of aryl groups include phenyl, biphenyl, naphthyl, 1-naphthyl and 2-naphthyl, and their derivatives.

[0255] The term "aliphatic" includes compounds with hydrocarbon chains, such as alkanes, alkenes, alkynes, and their derivatives.

[0256] The term "acyl" includes the group RCO—, where R is an organic group. An example is the acetyl group CH3CO—. This is referred to as "Ac" in this document.

[0257] The term "fatty acid" describes a carboxylic acid having an aliphatic chain, which may be fully saturated or partially unsaturated, and optionally attached to a functional group such as a hydroxyl group or a carboxyl group. The aliphatic chain may contain, for example, 6 to 26 carbon atoms and hydrogen atoms.

[0258] A peptide or aliphatic moiety is “acylated” when an alkyl or substituted alkyl group as defined above is bonded to one or more carbonyl {—(C═O)—} groups. Peptides are most commonly acylated at the N-terminus.

[0259] "ω-amino derivatives" include aliphatic moieties having terminal amino groups. Examples of ω-amino derivatives include aminoheptanoyl groups and amino acid side chain moieties of ornithine and lysine.

[0260] The term "heteroaryl" includes monocyclic and bicyclic aromatic rings containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur. Five- or six-membered heteroaryl groups are monocyclic heteroaromatic rings; examples include thiazoles, oxazoles, thiophenes, furans, pyrroles, imidazoles, isoxazoles, pyrazoles, triazoles, thiadiazoles, tetraazoles, oxadiazoles, pyridines, pyridazines, pyrimidines, and pyrazines. Bicyclic heteroaromatic rings include, but are not limited to, benzothiadiazoles, indole, benzothiophenes, benzofurans, benzimidazoles, benzoisoxazoles, benzothiazides, quinolines, benzotriazoles, benzoxazoles, isoquinolines, purines, furanopyridines, and thienopyridines.

[0261] "Amine" includes compounds containing an amine group (-NH2).

[0262] "Amide" includes compounds in which a trivalent nitrogen atom is attached to a carbonyl group (i.e., —CO—NH2), such as formamide, acetamide, and propionamide. Peptides are typically amidated at the C-terminus by adding an amine (—NH2) moiety to the C-terminal carboxyl group.

[0263] "Imine" includes compounds with carbon-nitrogen double bonds and nitrogen atoms also attached to hydrogen (NH═CH—R).

[0264] "Imine" includes compounds containing an imide group (-OC-NH-CO-).

[0265] "Nitriles" include compounds that are carboxylic acid derivatives and contain (-CN) groups that are bound to organic groups.

[0266] The term "halogen" is intended to include halogen atoms such as fluorine, chlorine, bromine, and iodine, as well as groups containing one or more halogen atoms, such as -CF3, etc.

[0267] Amino acids (including naturally occurring amino acids, protein amino acids, non-protein amino acids, post-translational modified amino acids, enzyme-synthesized amino acids, derived amino acids, stereoisomers and modifications of constructs or structures designed to mimic amino acids (peptide mimics), etc., all of the above) are sometimes referred to herein as “residues”.

[0268] A peptide or amino acid "analyte" is a non-amino acid molecule that mimics a peptide (amino acid chain) or a single amino acid residue.

[0269] "Significant degradation" refers to the N-terminal extension, C-terminal extension, degradation of both the N-terminus and C-terminus, or degradation of other regions of a non-naturally occurring melanocortin analogue caused by physiological enzymatic activity or other factors, in a manner or extent that leads to side effects. According to one aspect, a non-naturally occurring melanocortin analogue with C-terminal extension and not prone to significant degradation means that no more than 50% of the applied peptide causes side effects and / or exhibits a short half-life. In some aspects, no more than 25% of the applied peptide causes side effects and / or exhibits a short half-life. More preferably, in some aspects, less than 10% of the applied peptide causes side effects and / or exhibits a short half-life compared to a non-naturally occurring melanocortin analogue lacking C-terminal extension.

[0270] As used herein, "composition" or "pharmaceutical composition" refers to a mixture of an active ingredient and other chemical components (such as pharmaceutically acceptable carriers and / or excipients). As used herein, the term "active ingredient" refers to one or more non-naturally occurring melanocortin analogs in the present invention, for example, non-naturally occurring melanocortin analogs comprising a sequence according to formula (I). In some embodiments, other active ingredients may be incorporated into the pharmaceutical composition besides naturally occurring melanocortin analogs, for example, additional active ingredients chemically different from non-naturally occurring melanocortin analogs (e.g., appetite stimulants).

[0271] As used herein, a “pharmaceutically acceptable carrier and / or excipient” in a pharmaceutical composition means a carrier or diluent that does not cause significant irritation to an organism, does not eliminate the bioactivity and properties of the applied active ingredient, and / or does not interact adversely with other components of the composition in which it is contained. The term “carrier” encompasses any binder, diluent, filler, salt, buffer, stabilizer, lipid, or other material well known in the art for use in pharmaceutical formulations. The choice of carrier for use in a composition will depend on the intended mode of administration of the composition. Preparation of pharmaceutically acceptable carriers and formulations containing these materials is described, for example, in Remington's Pharmaceutical Sciences, 21st edition, edited by University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005, which is incorporated herein by reference in its entirety. An “excipient” in a pharmaceutical composition means an inert substance added to the composition to further facilitate the administration of the compound.

[0272] As used herein, the term "effective dose" or "therapeutic effective dose" refers to the amount of active ingredient administered that will, to a certain extent, alleviate one or more symptoms of the disease being treated. This result can be a reduction and / or relief of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. An appropriate "effective dose" can vary from person to person. In any individual case, an appropriate "effective dose" can be determined using techniques such as dose-escalation studies.

[0273] The term "after administration" refers to any duration following administration of a non-natural melanocorticoid analogue or a pharmaceutical composition thereof to a subject. "After administration" can also refer to the duration following completion of one dose or more than one dose (e.g., two doses, three doses, four doses, etc.). In some embodiments, "after administration" refers to completion of a dosing regimen comprising one or more doses. Unless otherwise stated, the duration covered by "after administration" can include seconds, minutes, hours, days, weeks, months, and years.

[0274] Appetite is typically assessed by a subject's and / or patient's desire to eat and / or the amount of food consumed. As used herein, appetite can be assessed using a daily questionnaire administered at a specific time of day or at random times. In the questionnaire, the subject or patient uses a scale ranging from 0 (not hungry at all) to 100 (extremely hungry) to rate their level of hunger and / or desire to eat more of a variety of foods.

[0275] "Cachexia" refers to a state of poor general health and malnutrition, characterized by weight loss, including weight loss, decreased muscle mass (skeletal muscle, smooth muscle, and / or cardiac muscle), decreased fat mass, or a combination thereof, and emaciation. It is often associated with and induced by certain diseases or conditions, such as, but not limited to, cancer, cystic fibrosis, or AIDS. The term "cancer cachexia" refers to cachexia induced by cancer.

[0276] "Anorexia" refers to loss of appetite, whether caused by medical, physiological, or psychological factors. Anorexia is often closely associated with cachexia observed in patients with advanced cancer and other diseases, and is often a trigger for cachexia.

[0277] Body Mass Index (BMI) is a numerical value derived from an individual's weight and height. Specifically, BMI is calculated by dividing weight (in kilograms) by the square of height (in meters). 2 ) Determined, and expressed in "kg / m 2 The unit "" indicates the normal BMI range. The "normal" BMI range is known to those skilled in the art and takes into account factors such as patient sex, age, height, race, and body type. Typically, a normal BMI range is approximately 18.5 kg / m². 2 Approximately 25 kg / m 2 .

[0278] The terms “treat,” “treatment,” and “treating” refer to a manner in which a pharmaceutical composition and / or a non-naturally occurring melanocorticoid analogue is provided to alleviate a disease outcome. This includes the use of administration techniques as described in the context of this invention. Therapeutic efficacy can be determined by various assessment methods as described in this invention, such as assessments of appetite, food consumption, body weight, muscle mass, fat mass, and the measurement of biomarkers.

[0279] The term "biomarker" refers to a biological output used as a measure of cellular response, whether for assessing response to treatment, disease states (such as cachexia), or as a predictor of clinical outcomes. Biomarkers are evaluated in the context of cells, tissues, or the entire organism. The term "disease" in this document refers to any condition that adversely affects a biological state. This includes weight-related conditions such as cachexia. Disease can also occur in the context of human and animal health.

[0280] The terms "subject" and "patient" refer to any person who is being evaluated for a disease or condition or who is receiving a therapeutic or pharmaceutical composition. This includes people who have not been diagnosed or confirmed with a disease or condition. It also includes people who have been diagnosed or confirmed with a disease or condition (such as loss of appetite, nausea, vomiting, anorexia, or cachexia).

[0281] As used herein, the term "control subject" refers to any subject used as the basis for comparison with a subject (e.g., a test subject). Control subjects include, but are not limited to, any subject who has not received treatment or a pharmaceutical composition (e.g., a non-naturally occurring melanocorticoid analog, a therapeutically effective amount of a non-naturally occurring melanocorticoid analog or a pharmaceutical composition thereof) or who has received a placebo.

[0282] As used herein, “renal dysfunction” includes any abnormality of kidney function that may be wholly or partially caused by kidney disease, kidney injury, or both. Renal dysfunction may also include any abnormality of kidney function caused by disease or condition of an organ other than the kidneys. Renal dysfunction may also include any abnormality of kidney function caused wholly or partially by kidney disease induced by kidney injury. Renal dysfunction may also include any abnormality of kidney function such as glomerulosclerosis, tubular necrosis, proximal tubular edema, or tubular fibrosis. Renal dysfunction may also include any abnormality of kidney function that occurs after a medical procedure (including, but not limited to, cardiac surgery or kidney transplantation). In some embodiments, renal dysfunction is associated with exacerbation of kidney inflammation.

[0283] As used herein, the term "kidney disease" includes chronic kidney disease (CKD), kidney failure, other kidney diseases, including but not limited to tubular diseases, vascular diseases, interstitial diseases, proteinuric kidney diseases, diabetic kidney diseases, acute tubular necrosis, acquired cystic kidney disease, renal amyloidosis, ectopic kidney, glomerular diseases, pulmonary hemorrhage nephritis, renal dysplasia, kidney infection, kidney stones, lupus nephritis, medullary sponge kidney, nephrotic syndrome, polycystic kidney disease, renal artery stenosis, renal tubular acidosis, simple renal cysts, or a single or isolated functional kidney.

[0284] As used herein, the term "kidney injury" (e.g., renal cell damage, kidney cell injury, or acute kidney injury) encompasses a range of kidney function losses, from minor to severe, or complete loss of function, caused by disease or condition of the kidney or other organs. For example, kidney injury may be caused by reduced blood flow to the kidneys due to factors such as dehydration, heart failure, sepsis, or certain medications. Kidney injury can also be caused by renal hypoxia. Kidney injury can also be caused by kidney diseases or conditions, such as inflammation of the kidney or part of the kidney, glomerulonephritis, or vasculitis. Kidney injury can also be caused by medications, such as antibiotics, antihypertensive drugs, chemotherapy agents, or dyes used in imaging procedures. For example, kidney injury may be caused by gentamicin. Kidney injury can be measured by a variety of symptoms and characteristics, such as glomerulosclerosis, tubular necrosis, proximal tubular edema, and / or tubular fibrosis. Kidney injury can be prerenal, renal, or postrenal.

[0285] All publications, patents, and published patent applications listed herein are incorporated herein by reference in their entirety, including but not limited to U.S. Patent Nos. 8,541,545 and 9,534,018.

[0286] Non-natural melanocortin analogues

[0287] In some aspects, the present invention provides a non-natural melanocortin analogue. In some embodiments, the non-natural melanocortin analogue comprises a sequence according to formula (I),

[0288] X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I)

[0289] in:

[0290] R 1The following groups are absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), acetylated trans-4-guanidino-proline (Ac-trans-Pro(guan)), acetylated cis-4-guanidino-proline (Ac-cis-Pro(guan)), trans-4-guanidino-proline (trans-Pro(guan)), cis-4-guanidino-proline (cis-Pro(guan)), acetylated cysteine, methylated D-phenylalanine, succinic acid, phthalic acid, tyrosine, D-tyrosine, dimethyltyrosine (Dmt), aspartic acid, glutaric acid, CO-cis-CH═CH—CO, n-valeryl group, n-hexyl Acyl groups, leucine, isoleucine, valine, valine, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated D-arginine, acetylated arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Ac-Tle), acetylated D-tertiary leucine (Ac-dTle), acetylated valine (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;

[0291] R 2 The following groups are absent or selected: proline, histidine, D-hydroxyproline (dHyp), hydroxyproline (Hyp), transPro(guan), cisPro(guan), D-aspartic acid, aspartic acid, D-glutamic acid, glutamic acid, glycine, lysine, alanine, D-alanine, tryptophan, cysteine, D-cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, valeryl group, hexanoyl group, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);

[0292] R 3The group consisting of the following is absent or selected: histidine, histidine methylated at position 1 or 3, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), trans-Pro(guan), cis-Pro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, alanylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptophanylarginine (Trp-Arg), glycine, phenylalanine, D-phenylalanine, succinic acid, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzozazepine-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzyl Acids (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthyl-2-carboxylic acid (Atc), 7-amino-7,8-dihydro-4H-(1,2,3)triazol-(1,5-a)(1,4)diazaphen-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazapheno-(4,3-b)indol-3(2H)-one (Aia) ), 1-amino-4-phenylcyclohexanecarboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octahydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indoline-2-carboxylic acid (Ioc), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe);

[0293] R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), (o-Phe)Phe, aspartic acid, biphenylalanine (Bip), dBip, glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), p-iodo-D-phenylalanine (p(I)dPhe), p-fluoro-D-phenylalanine (p(F)dPhe), and p-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);

[0294] R 5The following groups are not present or are selected from: arginine, homoarginine, ornithine, histidine, alanine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, D-glutamic acid, cysteine, and p(I)dPhe;

[0295] R 6 The group consisting of the following items is absent or selected: D-tryptophan, L-tryptophan, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, histidine, D-histidine, cysteine, Nal(1'), D-Nal(1'), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, Pen, dPen, alanine, and D-alanine;

[0296] R 7 The following groups are not present or are selected: glycine, aspartic acid, glutamic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diaminopropionic acid (Dap), methionine, proline, tryptophan, D-Nal(2'), ornithine, D-ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic);

[0297] R 8 It is absent or contains lysine or arginine;

[0298] R 9 It is absent or contains tryptophan;

[0299] R 10 It is absent or contains lysine;

[0300] R 11 To R 20 The following groups are not present independently or are selected from: cysteine, leucine, tyrosine, aspartic acid, leucine, isoleucine, valine, valine, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, arginine, histidine, hydroxyproline, D-hydroxyproline, D-proline, alanylglycine (Pro-Gly), D-Nal (2'), L-Nal (2'), Bip, ornithine, and tryptophan;

[0301] Where R 2 If it is a n-valeryl group or a n-hexanoyl group, then R 1 X 1 X 2and X 3 It does not exist;

[0302] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, β-homoproline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, piperazine-2-one ring, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated leucine.

[0303] X 2 The following groups are not present or are selected: D-threonine, D-proline, L-proline, β-homoproline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, piperazine-2-one ring, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0304] X 3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, β-homoproline, D-alanine, L-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, piperazine-2-one ring, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0305] Y 1 Choose the group consisting of the following: D-alanine, L-alanine, β-alanine, D-threonine, L-threonine, β-threonine, D-valine, L-valine, β-valine, (3-methyl)-β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, D-tert-leucine, L-tert-leucine, leucine, L-proline, D-proline, β-homoproline, piperazine-2-one ring, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;

[0306] Y2 The group consisting of or not present in the following groups is selected: D-proline, L-proline, β-homoproline, piperazine-2-one ring, D-threonine, L-threonine, β-threonine, D-valine, L-valine, β-valine, (3-methyl)-β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, D-tert-leucine, L-tert-leucine, ortholeucine, Hyp, dHyp, D-alanine, L-alanine, β-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;

[0307] Y 3 The group consisting of or not present in the following groups is selected: D-cysteine, L-cysteine, D-threonine, L-threonine, D-alanine, L-alanine, D-lysine, L-lysine, D-proline, L-proline, D-valine, L-valine, β-valine, (3-methyl)-β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, and piperazine-2-one ring;

[0308] Y 4 It is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine;

[0309] Y 5 It is absent or is either D-proline or D-valine;

[0310] Y 6 It is absent or is either D-proline or D-valine;

[0311] Y 7 It is absent or is either D-proline or D-valine;

[0312] Y 8 It is absent or is either D-proline or D-valine;

[0313] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[0314] When R 1 Or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 Or R 2 With R 7 or X 1 Disulfide bonds between them;

[0315] When R 2 and R5 To R 20 When any one of the components is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them;

[0316] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[0317] When R 1 Or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine, D-lysine, Dap, D-ornithine, or ornithine, R 1 Or R 2 With R 7 The side-chain lactam bridges between them;

[0318] When R 2 For lysine and R 7 When it is glutamic acid or aspartic acid, R 2 With R 7 The side-chain lactam bridges between them;

[0319] When R 1 Or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is glycine, proline or tryptophan, R 1 Or R 2 With R 8 The side-chain lactam bridges between them;

[0320] When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 Or R 4 With R 10 The side-chain lactam bridges between them;

[0321] When R 1 It is succinic acid or phthalic acid and R 7 When it is lysine, R 1 With R 7 The lactam closure between them; and

[0322] When R 2 It is succinic acid and R 7 When it is 2,3-diamino-propionic acid, R 2With R 7 The lactam closure between them;

[0323] X 1 X 2 X 3 Indicates the presence of an arbitrarily existing N-terminus; and

[0324] Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Indicates the C-terminus.

[0325] In some embodiments of equation (I):

[0326] R 1 The following groups are absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), trans-4-guanidino-proline (trans-Pro(guan)), cis-4-guanidino-proline (cis-Pro(guan)), acetylated trans-4-guanidino-proline (Ac-trans-Pro(guan)), acetylated cis-4-guanidino-proline (Ac-cis-Pro(guan)), acetylated cysteine, methylated D-phenylalanine, succinic acid, phthalic acid, tyrosine, D-tyrosine, dimethyltyrosine (Dmt), aspartic acid, glutaric acid, CO-cis-CH═CH—CO, n-valeryl Groups, hexanoyl group, leucine, isoleucine, valine, valine, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated D-arginine, acetylated arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Tle), acetylated D-tertiary leucine (dTle), acetylated valine (Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;

[0327] R 2The following groups are absent or selected: proline, histidine, D-hydroxyproline (dHyp), hydroxyproline (Hyp), transPro(guan), cisPro(guan), D-aspartic acid, aspartic acid, D-glutamic acid, glutamic acid, glycine, lysine, alanine, D-alanine, tryptophan, D-cysteine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, valeryl group, hexanoyl group, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);

[0328] R 3 The group consisting of the following is absent or selected: histidine, histidine methylated at position 1 or 3, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), trans-Pro(guan), cis-Pro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, alanylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptophanylarginine (Trp-Arg), glycine, phenylalanine, D-phenylalanine, succinic acid, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzozazepine-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzyl Acids (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthyl-2-carboxylic acid (Atc), 7-amino-7,8-dihydro-4H-(1,2,3)triazol-(1,5-a)(1,4)diazaphen-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazapheno-(4,3-b)indol-3(2H)-one (Aia) ), 1-amino-4-phenylcyclohexanecarboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octahydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indoline-2-carboxylic acid (Ioc), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe);

[0329] R 4Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), (o-Phe)Phe, aspartic acid, biphenylalanine (Bip), dBip, glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), p-iodo-D-phenylalanine (p(I)dPhe), p-fluoro-D-phenylalanine (p(F)dPhe), and p-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);

[0330] R 5 The following groups are not present or are selected from: arginine, homoarginine, ornithine, histidine, alanine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, D-glutamic acid, cysteine, and p(I)dPhe;

[0331] R 6 The group consisting of the following items is absent or selected: D-tryptophan, L-tryptophan, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, histidine, D-histidine, cysteine, Nal(1'), D-Nal(1'), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, Pen, dPen, alanine, and D-alanine;

[0332] R 7 The following groups are not present or are selected: glycine, aspartic acid, glutamic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diaminopropionic acid (Dap), methionine, proline, tryptophan, D-Nal(2'), ornithine, D-ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic);

[0333] R 8 It is absent or contains lysine or arginine;

[0334] R 9 It is absent or contains tryptophan;

[0335] R 10 It is absent or contains lysine;

[0336] R 11 To R 20The following groups are not present independently or are selected from: cysteine, leucine, tyrosine, aspartic acid, leucine, isoleucine, valine, valine, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, arginine, histidine, hydroxyproline, D-hydroxyproline, D-proline, alanylglycine (Pro-Gly), D-Nal (2'), L-Nal (2'), Bip, ornithine, and tryptophan;

[0337] Where R 2 If it is a n-valeryl group or a n-hexanoyl group, then R 1 X 1 X 2 and X 3 It does not exist;

[0338] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, β-homoproline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, piperazine-2-one ring, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated leucine.

[0339] X 2 The following groups are not present or are selected: D-threonine, D-proline, L-proline, β-homoproline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, piperazine-2-one ring, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0340] X 3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, β-homoproline, D-alanine, L-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, piperazine-2-one ring, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0341] Y 1 Choose the group consisting of the following: D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, D-tert-leucine, L-tert-leucine, leucine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;

[0342] Y 2 The group consisting of the following items is absent or selected: D-proline, L-proline, D-valine, L-valine, D-tert-leucine, L-tert-leucine, leucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;

[0343] Y 3 The group consisting of the following is absent or selected: D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;

[0344] Y 4 It is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine;

[0345] Y 5 It is absent or is either D-proline or D-valine;

[0346] Y 6 It is absent or is either D-proline or D-valine;

[0347] Y 7 It is absent or is either D-proline or D-valine;

[0348] Y 8 It is absent or is either D-proline or D-valine;

[0349] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[0350] When R 1 Or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 Or R 2 With R 7 or X 1 Disulfide bonds between them;

[0351] When R 2 and R 5 To R20 When any one of the following is selected from the group consisting of D-cysteine, cysteine, Dap, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them;

[0352] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[0353] When R 1 Or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine, D-lysine, D-ornithine or ornithine, R 1 Or R 2 With R 7 The side-chain lactam bridges between them;

[0354] When R 2 For lysine and R 7 When it is glutamic acid or aspartic acid, R 2 With R 7 The side-chain lactam bridges between them;

[0355] When R 1 Or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 Or R 2 With R 8 The side-chain lactam bridges between them;

[0356] When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 Or R 4 With R 10 The side-chain lactam bridges between them;

[0357] When R 1 It is succinic acid or phthalic acid and R 7 When it is lysine, R 1 With R 7 The lactam closure between them; and

[0358] When R 2 It is succinic acid and R 7 When it is 2,3-diamino-propionic acid, R 2 With R 7The lactam closure between them;

[0359] X 1 X 2 X 3 Indicates the presence of an arbitrarily existing N-terminus; and

[0360] Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Indicates the C-terminus.

[0361] In some embodiments of equation (I):

[0362] R 1 The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), trans-4-guanidino-proline (trans-Pro(guan)), cis-4-guanidino-proline (cis-Pro(guan)), acetylated trans-4-guanidino-proline (Ac-trans-Pro(guan)), acetylated cis-4-guanidino-proline (Ac-cis-Pro(guan)), acetylated cysteine, tyrosine, D-tyrosine, dimethyltyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, and n-valine (N Alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Tle), acetylated D-tertiary leucine (dTle), acetylated normal valine (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;

[0363] R 2 The following groups are absent or selected: proline, histidine, D-hydroxyproline (dHyp), hydroxyproline (Hyp), transPro(guan), cisPro(guan), D-aspartic acid, aspartic acid, D-glutamic acid, glutamic acid, glycine, lysine, alanine, D-alanine, tryptophan, D-cysteine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);

[0364] R3 The group consisting of the following is absent or selected: histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), trans-Pro(guan), cis-Pro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, alanylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptophanylarginine (Trp-Arg), glycine, phenylalanine, D-phenylalanine, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzodiazepine-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1 -Aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthyl-2-carboxylic acid (Atc), 7-amino-7,8-dihydro-4H-(1,2,3)triazol-(1,5-a)(1,4)diazazo-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazazopheno-(4,3-b)indol-3(2H)-one (Aia), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octahydroindol-2-carboxylic acid (Oic), 1-amino-1-cyclohexane-carboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indololin-2-carboxylic acid (Ioc), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentane-carboxylic acid (Cpe);

[0365] R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), dBip, glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), p-iodo-D-phenylalanine (p(I)dPhe), p-fluoro-D-phenylalanine (p(F)dPhe), and p-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);

[0366] R 5 The following groups are not present or are selected from: arginine, homoarginine, ornithine, histidine, alanine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, D-glutamic acid, cysteine, and p(I)dPhe;

[0367] R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, histidine, D-histidine, cysteine, Nal(1'), D-Nal(1'), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, Pen, dPen, alanine, and D-alanine;

[0368] R 7 The following groups are not present or are selected: glycine, aspartic acid, glutamic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diaminopropionic acid (Dap), methionine, proline, tryptophan, D-Nal(2'), ornithine, D-ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic);

[0369] R 8 It is absent or contains lysine or arginine;

[0370] R 9 It is absent or contains tryptophan;

[0371] R 10 It is absent or contains lysine;

[0372] R 11 To R 20 It does not exist;

[0373] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated n-leucine;

[0374] X 2 The group consisting of the following is absent or selected: D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0375] X3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0376] Y 1 The following groups are not present or are selected: D-alanine, L-alanine, D-valine, L-valine, D-tert-leucine, L-tert-leucine, leucine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;

[0377] Y 2 The group consisting of the following items is absent or selected: D-proline, L-proline, D-valine, L-valine, D-tert-leucine, L-tert-leucine, leucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;

[0378] Y 3 The group consisting of the following is absent or selected: D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;

[0379] Y 4 It is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine;

[0380] Y 5 It is absent or is either D-proline or D-valine;

[0381] Y 6 It is absent or is either D-proline or D-valine;

[0382] Y 7 It is absent or is either D-proline or D-valine;

[0383] Y 8 It is absent or is either D-proline or D-valine;

[0384] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[0385] When R 1 Or R 2 For cysteine ​​and R7 or X 1 When it is cysteine, R 1 Or R 2 With R 7 or X 1 Disulfide bonds between them;

[0386] When R 2 and R 5 To R 20 When any one of the following is selected from the group consisting of D-cysteine, cysteine, Dap, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them;

[0387] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[0388] When R 1 Or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine, D-lysine, D-ornithine or ornithine, R 1 Or R 2 With R 7 The side-chain lactam bridges between them;

[0389] When R 2 For lysine and R 7 When it is glutamic acid or aspartic acid, R 2 With R 7 The side-chain lactam bridges between them;

[0390] When R 1 Or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 Or R 2 With R 8 The side-chain lactam bridges between them;

[0391] When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 Or R 4 With R 10 The side-chain lactam bridges between them;

[0392] The conditions are:

[0393] When R 2 When it is dAsp, then R 7 Not for dLys;

[0394] When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7 Not Arg-Trp-Lys; and

[0395] When Y 1 For dPro, Y 2 For dVal, Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified.

[0396] In some embodiments, non-natural melanocortin analogues comprise the sequence of formula (I), wherein:

[0397] R 1 The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), trans-4-guanidino-proline (transPro(guan)), cis-4-guanidino-proline (cisPro(guan)), acetylated trans-4-guanidino-proline (Ac-transPro(guan)), acetylated cis-4-guanidino-proline (Ac-cisPro(guan)), tyrosine, D-tyrosine, dimethyltyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid;

[0398] R 2 The group consisting of the following is absent or selected: proline, histidine, D-hydroxyproline (dHyp), transPro(guan), cisPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, leucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine.

[0399] R 3The group consisting of the following is absent or selected: histidine, L-proline, trans-Pro(guan), cis-Pro(guan), D-valine, glutamic acid, tryptophanyl arginine (Trp-Arg), glycine, D-leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzozazepine-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazol-(1,5-a)(1,4)diazepine-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazazepine(4,3-b)indol-3(2H)-one (Aia), octahydroindol-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), and indololin-2-carboxylic acid (Ioc).

[0400] R 4 Select the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, dBip, glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-iodo-D-phenylalanine (p(I)dPhe), p-fluoro-D-phenylalanine (p(F)dPhe), and p-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);

[0401] R 5 The following groups are not present or are selected: arginine, homoarginine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(I)dPhe;

[0402] R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-phenylalanine, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1'), Aba, Ata, D-tyrosine, Pen, dPen and D-alanine;

[0403] R 7 The group consisting of the following is absent or selected: glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2') and tetrahydro-isoquinoline-3-carboxylic acid (Tic);

[0404] R 8 It may be absent or contain lysine;

[0405] R 9 To R 20 It does not exist;

[0406] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated n-leucine;

[0407] X 2 It may be absent or contain D-proline;

[0408] X 3 It does not exist;

[0409] Y 1 The group consisting of the following is absent or selected: D-valine, D-tert-leucine, L-tert-leucine, ortholeucine, and D-proline;

[0410] Y 2 The group consisting of the following is absent or selected: D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, ortholeucine, and glycine;

[0411] Y 3 The group consisting of the following is absent or selected: D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;

[0412] Y 4 It is absent or is either D-aspartic acid or aspartic acid;

[0413] Y 5 To Y 8 It does not exist;

[0414] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[0415] When R 1 For cysteine ​​and R 7 When it is cysteine, R 1 With R 7 Disulfide bonds between them;

[0416] When R 1 It is leucine and R 7When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[0417] When R 1 Or R 2 It is glutamic acid or aspartic acid and R 7 When it is lysine or Dap, R 1 Or R 2 With R 7 The side-chain lactam bridges between them;

[0418] When R 2 For lysine and R 7 When it is glutamic acid or aspartic acid, R 2 With R 7 The side-chain lactam bridges between them;

[0419] When R 1 Or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 Or R 2 With R 8 The side-chain lactam bridges between them;

[0420] The conditions are:

[0421] When R 2 When it is dAsp, then R 7 Not for dLys;

[0422] When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7 Not Arg-Trp-Lys;

[0423] When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified;

[0424] When R 3 For Aba, Ata, or Aia, R 6 When it is Aia, then R 4 Not dNal(2'), or R 4For dNal(2') and R 5 Not for Arg;

[0425] When R 4 When R is p(Cl)dPhe, then 3 Not Pro or His;

[0426] When R 4 When the value is p(I)dPhe, this non-natural melanocortin analogue is obtained through R. 1 With R 7 The side-chain lactam bridged cyclization between them, and R 2 and R 3 At least one of them is Pro;

[0427] When Y 2 To Y 4 If it does not exist, then Y 1 It is absent or contains ortholeucine;

[0428] When R 2 For Pro or Y 2 When it is Hyp, then R 3 Not for Pro;

[0429] When R 3 R 5 Or R 6 If it does not exist, then this non-natural melanocortin analogue is obtained through R. 1 With R 7 The cyclization of lactams between them, or X 1 To X 2 It exists and is Ac-dVal-dPro;

[0430] When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys or Cys-Pro-dNal(2')-Arg-Trp-Cys, then R 1 Not Ac-Nle or Y 1 To Y 2 Not dVal-dPro, dVal-dVal, or dPro-dPro; and

[0431] When this non-natural melanocortin analogue is administered via R 2 With R 8 When the lactam bridge between them is cyclized, then R 3 Not His or Y 1 Not dVal.

[0432] In some embodiments, non-natural melanocortin analogues comprise the sequence of formula (I), wherein:

[0433] R 1 The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), trans-4-guanidino-proline (transPro(guan)), cis-4-guanidino-proline (cisPro(guan)), acetylated trans-4-guanidino-proline (Ac-transPro(guan)), acetylated cis-4-guanidino-proline (Ac-cisPro(guan)), tyrosine, D-tyrosine, dimethyltyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid;

[0434] R 2 The group consisting of the following is absent or selected: proline, histidine, D-hydroxyproline (dHyp), transPro(guan), cisPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, leucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine.

[0435] R 3 The group consisting of the following is absent or selected: histidine, L-proline, trans-Pro(guan), cis-Pro(guan), D-valine, glutamic acid, tryptophanyl arginine (Trp-Arg), glycine, D-leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzozazepine-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazol-(1,5-a)(1,4)diazepine-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazazepine(4,3-b)indol-3(2H)-one (Aia), octahydroindol-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), and indololin-2-carboxylic acid (Ioc).

[0436] R 4Select the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, dBip, glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-iodo-D-phenylalanine (p(I)dPhe), p-fluoro-D-phenylalanine (p(F)dPhe), and p-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);

[0437] R 5 The following groups are not present or are selected: arginine, homoarginine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(I)dPhe;

[0438] R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-phenylalanine, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1'), Aba, Ata, D-tyrosine, Pen, dPen and D-alanine;

[0439] R 7 The group consisting of the following is absent or selected: glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2') and tetrahydro-isoquinoline-3-carboxylic acid (Tic);

[0440] R 8 It may be absent or contain lysine;

[0441] R 9 To R 20 It does not exist;

[0442] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated n-leucine;

[0443] X 2 It may be absent or contain D-proline;

[0444] X 3 It does not exist;

[0445] Y 1 The group consisting of the following is absent or selected: D-valine, D-tert-leucine, L-tert-leucine, ortholeucine, and D-proline;

[0446] Y 2 The group consisting of the following is absent or selected: D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, ortholeucine, and glycine;

[0447] Y 3 The group consisting of the following is absent or selected: D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;

[0448] Y 4 It is absent or is either D-aspartic acid or aspartic acid;

[0449] Y 5 To Y 8 It does not exist;

[0450] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[0451] When R 1 For cysteine ​​and R 7 When it is cysteine, R 1 With R 7 Disulfide bonds between them;

[0452] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[0453] When R 1 Or R 2 It is glutamic acid or aspartic acid and R 7 When it is lysine or Dap, R 1 Or R 2 With R 7 The side-chain lactam bridges between them;

[0454] When R 2 For lysine and R 7 When it is glutamic acid or aspartic acid, R 2 With R 7 The side-chain lactam bridges between them;

[0455] When R1 Or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 Or R 2 With R 8 The side-chain lactam bridges between them;

[0456] The condition is that the non-natural melanocortin analogue does not contain a sequence selected from the group consisting of:

[0457] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-NH2 (SEQ ID NO: 139);

[0458] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-NH2 (SEQ ID NO: 140);

[0459] Ac-Nle-c(Asp-Aba-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 207);

[0460] Ac-Nle-c(Asp-Aia-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 208);

[0461] Ac-Nle-c(Asp-Ata-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 209),

[0462] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dVal-dPro-NH2 (SEQ IDNO: 192);

[0463] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-dVal-dPro-NH2 (SEQ IDNO: 193);

[0464] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dPro-NH2 (SEQ ID NO: 190);

[0465] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-dPro-NH2(SEQ ID NO:191);

[0466] Ac-Nle-c(Asp-Pro-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:391);

[0467] Ac-Nle-c(Asp-His-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:396);

[0468] Ac-Nle-c(Asp-His-Arg-p(I)dPhe-Arg-Tic-Lys)-dVal-dPro-NH2(SEQ ID NO:376);

[0469] Ac-Nle-c(Asp-Pro-p(I)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:392);

[0470] Ac-Nle-c(Asp-His-p(I)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:397);

[0471] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-NH2(SEQ ID NO:137);

[0472] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dPro-NH2(SEQ ID NO:138);

[0473] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-OH(SEQ ID NO:127);

[0474] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO:129);

[0475] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-Hyp-NH2(SEQ ID NO:131);

[0476] Ac-Nle-c(Asp-Pro-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:198);

[0477] Ac-Nle-c(Asp-Pro-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:401);

[0478] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Aia-Lys)-dVal-dPro-NH2(SEQ ID NO:114);

[0479] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:3;B07);

[0480] Ac-Nle-Asp-Pro-dNal(2')-Arg-Trp-Lys-dVal-dPro-NH2(SEQ ID NO:13;A1);

[0481] Ac-Nle-c(Asp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:71);

[0482] Ac-Nle-c(Cys-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:46);

[0483] Ac-Nle-c(Asp-Pro-dNal(2')-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:97);

[0484] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Lys)-dVal-dPro-NH2(SEQ ID NO:112);

[0485] Ac-Nle-c(Asp-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:5;D1);

[0486] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2(SEQ ID NO:8;D2);

[0487] Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:42);

[0488] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO:286);

[0489] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO:287);

[0490] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dPro-dVal-NH2(SEQ ID NO:288);

[0491] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dPro-dVal-NH2(SEQ ID NO:289);

[0492] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:291);

[0493] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH2(SEQ ID NO:292);

[0494] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH2(SEQ ID NO:293);

[0495] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO:420);

[0496] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 421);

[0497] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 424);

[0498] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 425); and

[0499] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 426).

[0500] In some embodiments, non-naturally occurring melanocortin analogs have one or more β-hairpin (β-hairpin) and / or β-turn (β-turn) structures. In some embodiments, R according to the sequence of formula (I) 3 (It can be D-proline, L-proline, hydroxyproline, D-hydroxyproline, D-alanine, D-methionine, D-valine, alanylglycine (Pro-Gly), glycine, trans-Pro(guan), cis-Pro(guan)) provides β-hairpin and / or β-turn structures for non-naturally occurring melanocortin analogs. In some embodiments, if present, disulfide bonds according to the sequence of formula (I) provide β-hairpin and / or β-turn structures for non-naturally occurring melanocortin analogs.

[0501] In some embodiments, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with a functional group selected from the group consisting of: acyl groups, imine groups, amide groups, urea groups, carbamate groups, sulfonamide groups, and alkylamine groups.

[0502] In some embodiments, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with an acyl group. In some embodiments, the acyl group is an acetyl group (e.g., In some embodiments, the acyl group is a formyl group (e.g., ).

[0503] In some embodiments, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with an imine group.

[0504] In some embodiments, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with an amide group. In some embodiments, the amide group is a pyroglutamyl (pGlu) group (e.g., In some embodiments, the amide group is derived from a fatty acid (e.g., ).

[0505] Other examples of N-terminal modifications include, but are not limited to, (urea group), (carbamate group) (Sulfanamide group) (alkylamine group).

[0506] In some embodiments, if present, the N-terminus of the non-naturally occurring melanocortin analogue is not modified.

[0507] As discussed above, Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 The C-terminus represents a non-naturally occurring melanocortin analogue. In some embodiments, Y... 1 To Y 8 It does not exist. In some embodiments, Y 1 Existence and Y 2 To Y 8 It does not exist.

[0508] In some embodiments, Y 1 and Y 2 Existence and Y 3 To Y 8 It does not exist. In some embodiments, Y 3 To Y 8 It does not exist, and Y 1 It is D-valine and Y 2 It is D-proline, or Y-proline. 1 It is D-proline and Y 2 It is D-valine.

[0509] In some embodiments, Y 3 Existence and Y 4 To Y 8 It does not exist. In some embodiments, Y 3 Existence and Y 4 To Y 8 It does not exist, and (i)Y 1 (ii)Y is D-valine or D-proline. 2D-valine or D-proline and / or (iii) Y 3 It is D-valine or D-proline. In some embodiments, Y... 3 Existence and Y 4 To Y 8 It does not exist, and (i)Y 1 For D-valine, Y 2 It is D-valine and Y 3 For D-proline, (ii)Y 1 For D-proline, Y 2 It is D-valine and Y 3 For D-valine, or (iii)Y 1 For D-valine, Y 2 It is D-proline and Y 3 It is D-valine.

[0510] In some embodiments, Y 3 and Y 4 It exists, and Y 5 To Y 8 It does not exist. In some embodiments, Y 3 and Y 4 It exists, and Y 5 To Y 8 It does not exist, and (i)Y 1 (ii)Y is D-valine or D-proline. 2 It is D-valine or D-proline, (iii)Y 3 It is D-valine or D-proline, and / or (iv) Y 4 It is D-valine or D-proline. In some embodiments, Y... 3 and Y 4 It exists, and Y 5 To Y 8 It does not exist, and (i)Y 1 For D-valine, Y 2 For D-valine, Y 3 It is D-valine and Y 4 For D-proline, (ii)Y 1 For D-proline, Y 2 For D-valine, Y 3 It is D-valine and Y 4 For D-valine, (iii)Y 1 For D-valine, Y 2 For D-proline, Y 3 It is D-valine and Y 4为D- Valine, or (iv)Y 1 For D-valine, Y 2For D-valine, Y 3 It is D-proline and Y 4 It is D-valine.

[0511] In some embodiments, the C-terminus includes additional derivatives to extend the length of the C-terminus of non-naturally occurring melanocortin analogs. Exemplary additional C-termini include, but are not limited to, Y... 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Y 9 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Y 9 Y 10 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Y 9 Y 10 Y 11 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Y 9 Y 10 Y 11 Y 12 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Y 9 Y 10 Y 11 Y 12 Y 13 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y7 AND 8 AND 9 AND 10 AND 11 AND 12 AND 13 AND 14 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND 9 AND 10 AND 11 AND 12 AND 13 AND 14 AND 15 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND 9 AND 10 AND 11 AND 12 AND 13 AND 1 4 AND 15 AND 16 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND 9 AND 10 AND 11 AND 12 AND 13 AND 14 AND 15 AND 16 AND 17 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND 9 AND 10 AND 11 AND 12 AND 13 AND 14 AND15 AND 16 AND 17 AND 18 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND 9 AND 10 AND 11 AND 12 AND 13 AND 14 AND 15 AND 16 AND 17 AND 18 AND 19 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND 9 AND 10 AND 11 AND 12 AND 13 AND 14 AND 15 AND 16 AND 17 AND 18 AND 19 AND 20 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND 9 AND 10 AND 11 AND 12 AND 13 AND 14 AND 15 AND 16 AND 17 AND 18 AND 19 AND 20 AND 21 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND8 Y 9 Y 10 Y 11 Y 12 Y 13 Y 14 Y 15 Y 16 Y 17 Y 18 Y 19 Y 20 Y 21 Y 22 、Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Y 9 Y 10 Y 11 Y 12 Y 13 Y 14 Y 15 Y 16 Y 17 Y 18 Y 19 Y 20 Y 21 Y 22 Y 23 and Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Y 9 Y 10 Y 11 Y 12 Y 13 Y 14 Y 15 Y 16 Y 17 Y 18 Y 19 Y 20 Y 21 Y 22 Y 23 Y 24 etc., where Y 9 to Y 24 (if present) are each independently D-proline or D-valine.

[0512] In some embodiments, if present, the C-terminus of the non-naturally occurring melanocortin analog is modified with a functional group selected from the group consisting of amide groups, ester groups, and aldehyde groups.

[0513] In some embodiments, if present, the C-terminus of a non-naturally occurring melanocortin analogue is fitted with an amide group (e.g., Modification. In the sequence of formula (I), non-natural melanocortin analogs with C-terminal amide modification can be represented by a terminal -NH2, for example in the sequence Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-Pro-NH2 (SEQ ID NO:126). In some embodiments, the amide group is an N-alkylamide group (e.g., ) or N-arylamide group. In some embodiments, the N-arylamide group is a p-nitroaniline group (pNA) (e.g., ) or 7-amino-4-methylcoumarin (AMC) (e.g., ).

[0514] In some embodiments, if present, the C-terminus of a non-naturally occurring melanocortin analogue is bound with an ester group (e.g., Modification.

[0515] In some embodiments, if present, the C-terminus of a non-naturally occurring melanocortin analogue is capped with an aldehyde (e.g., Modification.

[0516] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is unmodified. In the sequence of formula (I), the non-naturally occurring melanocortin analog with an unmodified C-terminus can be represented by -OH, for example in the sequence Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-OH (SEQ ID NO:127), or by the absence of a C-terminal group, for example in the sequence Ac-Nle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro(SEQ ID NO:2; B07a). In some embodiments, the C-terminus of the non-natural melanocortin analogue is not modified, and the sequence of formula (I) is Ac-Nle- c (Asp-Pro-dNal2'-Arg-Trp-Lys)-dVal-dPro (SEQ ID NO: 2).

[0517] In some embodiments, R 1 It does not exist, and R2 It is D-aspartic acid. In some embodiments, R 1 It is acetylated leucine, and R 2 It is D-aspartic acid.

[0518] In some embodiments, X 1 X 2 and X 3 It does not exist. In some embodiments, X 1 Existence and X 2 and X 3 It does not exist.

[0519] In some embodiments, R 4 Not D-phenylalanine. In some embodiments, R 4 For D-Nal(2'). When R 4 When it is D-Nal(2'), the non-natural melanocortin analogues of the present invention can act as melanocortin receptor antagonists.

[0520] In some embodiments, the non-naturally occurring melanocortin analogues of the present invention are cyclized. For example, the non-naturally occurring melanocortin analogues can be partially cyclized by selecting from the group consisting of: when R 1 Or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 Or R 2 With R 7 or X 1 disulfide bonds between; when R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them; when R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between; when R 1 It is aspartic acid and R 5-8 When either of them is lysine, R 1 With R 5-8 Any of the side chain lactam bridges in R; 1 For lysine and R 6 When it is aspartic acid, R 1 With R 6 The side-chain lactam bridge between; when R 2 For lysine and R7 When it is glutamic acid or aspartic acid, R 2 With R 7 The side-chain lactam bridge between; when R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine, Dap, or ornithine, R 2 With R 7 The side-chain lactam bridge between; when R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is glycine, proline, or tryptophan, R 2 With R 8 The side-chain lactam bridge between; when R 2 Or R 4 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 Or R 4 With R 10 The side-chain lactam bridge between; when R 1 It is succinic acid or phthalic acid and R 7 When it is lysine, R 1 With R 7 The lactam closure between; and / or when R 2 It is succinic acid and R 7 When it is 2,3-diamino-propionic acid, R 2 With R 7 The lactam closure between them. Cycloning can also begin from any X residue (optionally a stable N-terminal residue). For example, X 2 It could be aspartic acid, which can be used for cyclization.

[0521] In some embodiments, R 1 R 2 and R 7 Existence and R 8 To R 20 It does not exist, and the sequence of equation (I) passes through R. 2 and R 7 Via lactam cyclization. In some embodiments, R 1 It is acetylated leucine, R 2 It is aspartic acid, R 3 Select the group consisting of free proline, hydroxyproline, and D-hydroxyproline, R 4 For D-Nal(2'), R 5 For arginine, R 6 For D-tryptophan or L-tryptophan, R 7 For lysine, Y 1 It is D-valine and / or Y2 It is D-proline.

[0522] In some embodiments, the sequence of equation (I) is Ac-Nle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3; B07) or Ac-Nle- c (Asp-Hyp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:4; D3), where c represents through R 2 and R 7 Cyclation via lactam bonds.

[0523] In some embodiments, R 1 R 2 R 7 and R 8 Existence and R 9 To R 20 It does not exist, and the sequence of equation (I) passes through R. 2 and R 8 Via lactam cyclization. In some embodiments, R 1 It is acetylated leucine, R 2 It is aspartic acid, R 3 Select the group consisting of proline, hydroxyproline, D-hydroxyproline, phenylalanine, and histidine, R 4 For histidine or dNal(2'), R 5 For dNal(2') or arginine, R 6 Select the group consisting of free arginine, D-tryptophan, and L-tryptophan, R 7 For tryptophan or proline, R 8 For lysine, Y 1 Select the group consisting of D-valine, D-leucine, and D-isoleucine, and / or Y 2 It is D-proline.

[0524] In some embodiments, the sequence of equation (I) is selected from the group consisting of the following:

[0525] Ac-Nle- c (Asp-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 5; D1);

[0526] Ac-Nle- c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 6; D1γ);

[0527] Ac-Nle- c (Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dTle-dPro-NH2 (SEQ ID NO:7; D1δ);

[0528] Ac-Nle- c (Asp-His-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 8; D2);

[0529] Ac-Nle- c (Asp-Hyp-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 9; D4); and

[0530] Ac-Nle- c (Asp-Pro-His-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 10; D5),

[0531] Where c represents through R 2 and R 8 Cyclation via lactam bonds.

[0532] In some embodiments, R 1 To R 2 and R 7 To R 10 Existence and R 11 To R 20 It does not exist, and the sequence of equation (I) passes through R. 2 and R 10 Cyclation via lactam bonds. In some embodiments, the sequence of formula (I) is Ac-Nle- c (Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:11; D1α), where c represents the result of passing through R 2 and R 10 Cyclation via lactam bonds.

[0533] In some embodiments, R 1 To R 2 and R 7 To R10 Existence and R 11 To R 20 It does not exist, and the sequence of equation (I) passes through R. 4 and R 10 Cyclation via a lactam bond. In some embodiments, the sequence of formula (I) is Ac-Nle-Phe-Phe- c (Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:12; D1β), where c represents the result of passing through R 4 and R 10 Cyclation via lactam bonds.

[0534] In some embodiments, the sequence of formula (I) is linear. In some embodiments, the sequence of formula (I) is Ac-Nle-Asp-Pro-dNal(2')-Arg-Trp-Lys-dVal-dPro-NH2 (SEQ ID NO: 13; A1). In some embodiments, the sequence of formula (I) is Ac-Nle-Pro-dNal(2')-Arg-Trp-dVal-dPro-NH2 (SEQ ID NO: 14; A2).

[0535] In some embodiments of the sequence of equation (I), R 1 It is acetylated leucine. Alternatively, in some embodiments, R 1 R is an acetylated amino acid other than acetylated leucine. In some embodiments, R 1 It is a non-acetylated amino acid. In some embodiments, the sequence of formula (I) is selected from the group consisting of:

[0536] Ac-dArg- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 15);

[0537] Ac-dMet- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 16);

[0538] Ac-dIle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 17);

[0539] Ac-dLeu- c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:18);

[0540] Ac-dVal- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:19);

[0541] Ac-dAla- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:20);

[0542] Ac-Ala- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:21);

[0543] Ac-Tle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:22);

[0544] Ac-dTle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:23);

[0545] Ac-dNle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:24);

[0546] Ac-Nva- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:25);

[0547] Ac-Gly- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:26);

[0548] Ac-dPro- c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:27);

[0549] Ac-dCys- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:28);

[0550] Ac-dPhe- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:29);

[0551] Ac-dTyr- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:30);

[0552] Ac-dGln- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:31);

[0553] Ac-dAsn- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:32);

[0554] Ac-trans-Pro(guan)-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:33);

[0555] Ac-cis-Pro(guan)-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:34);

[0556] dTyr-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:35);

[0557] Tyr-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:36);

[0558] Dmt-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 37);

[0559] Ac-Glu-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 38); and

[0560] Ac-Asn-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:39),

[0561] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[0562] In some embodiments, when the sequence of equation (I) is passed through R 2 and R 7 When cyclized, then R 2 For Asp and R 7 For Lys. Alternatively, in some embodiments, when the sequence of equation (I) is passed through R 2 and R 7 When cyclized, then R 2 For those other than Asp that can interact with R 7 The amino acid that forms a bond with the residue and R 7 For those other than Lys that can interact with R 2 Amino acids that form bonds with residues at a certain point. For example, when R... 2 It consists of amino acids other than Arg and R 7 When R is an amino acid other than Lys, 2 The residues at that position can interact with R 7 The residues at the position form bonds, such as lactam bonds or disulfide bonds. In some embodiments, the sequence of formula (I) is selected from the group consisting of:

[0563] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 40);

[0564] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 41);

[0565] Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:42);

[0566] Ac-Nle-c(dCys-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:43);

[0567] Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:44);

[0568] Ac-Nle-c(dCys-Pro-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:45);

[0569] Ac-Nle-c(Cys-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:46);

[0570] Ac-Nle-c(dCys-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:47);

[0571] Ac-Nle-c(Cys-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:48);

[0572] Ac-Nle-c(dCys-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:49);

[0573] Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:50);

[0574] Ac-Nle-c(dCys-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:51);

[0575] Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:52);

[0576] Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:53);

[0577] Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:54);

[0578] Ac-Nle-c(dPen-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:55);

[0579] Ac-Nle-c(dPen-Pro-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO:56);

[0580] Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO:57);

[0581] Ac-Nle-c(Cys-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:58);

[0582] Ac-Nle-c(dCys-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:59);

[0583] Ac-Nle-c(Pen-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:60);

[0584] Ac-Nle-c(Pen-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:61);

[0585] Ac-Nle-c(Pen-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:62);

[0586] Ac-Nle-c(dPen-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:63);

[0587] Ac-Nle-c(dPen-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 64);

[0588] Ac-Nle-c(Pen-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 65);

[0589] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 66);

[0590] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-dOrn)-dVal-dPro-NH2 (SEQ ID NO: 67);

[0591] Ac-Nle-c(Glu-Pro-dNal(2')-Arg-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 68);

[0592] Ac-Nle-c(Glu-Pro-dNal(2')-Arg-Trp-dOrn)-dVal-dPro-NH2 (SEQ ID NO: 69); and

[0593] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO:70),

[0594] Where c represents through R 2 and R 6 Or R 7 Cycling via lactam bonds or disulfide bonds.

[0595] In some embodiments of the sequence of equation (I), R 3 For Pro. Alternatively, in some embodiments, R 3 The amino acid is absent or is not a protein other than Pro. In some embodiments, the sequence of formula (I) is selected from the group consisting of:

[0596] Ac-Nle-c(Asp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:71);

[0597] Ac-Nle-c(Asp-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:72);

[0598] Ac-Nle-c(Asp-dPro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:73);

[0599] Ac-Nle-c(Asp-dAla-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:74);

[0600] Ac-Nle-c(Asp-dMet-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:75);

[0601] Ac-Nle-c(Asp-Pro-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:76);

[0602] Ac-Nle-c(Asp-Gly-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:77);

[0603] Ac-Nle-c(Asp-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:78);

[0604] Ac-Nle-c(Asp-Leu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:79);

[0605] Ac-Nle-c(Asp-Ile-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:80);

[0606] Ac-Nle-c(Asp-Val-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:81);

[0607] Ac-Nle-c(Asp-dLeu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:82);

[0608] Ac-Nle-c(Asp-dIle-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:83);

[0609] Ac-Nle-c(Asp-dVal-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:84);

[0610] Ac-Nle-c(Asp-Trp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:85);

[0611] Ac-Nle-c(Asp-dTrp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:86);

[0612] Ac-Nle-c(Asp-trans-Pro(guan)-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:87);

[0613] Ac-Nle-c(Asp-cis-Pro(guan)-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:88);

[0614] Ac-Nle-c(Asp-Val-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:89);

[0615] Ac-Nle-c(Asp-Ile-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:90);

[0616] Ac-Nle-c(Asp-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:91);

[0617] Ac-Nle-c(Asp-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:92);

[0618] Ac-Nle-c(Asp-Arg-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:93);

[0619] Ac-Nle-c(Asp-dLeu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:94);

[0620] Ac-Nle-c(Asp-dAla-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:95); and

[0621] Ac-Nle-c(Asp-dMet-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:96), where c represents the result of passing through R 2 and R 7 Cyclation via lactam bonds.

[0622] In some embodiments of the sequence of equation (I), R 5 For Arg. Alternatively, in some embodiments, R 5 The amino acid is absent or consists of an amino acid other than Arg. In some embodiments, the sequence of formula (I) is selected from the group consisting of:

[0623] Ac-Nle-c(Asp-Pro-dNal(2')-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:97);

[0624] Ac-Nle-c(Asp-Pro-dNal(2')-Lys-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:98);

[0625] Ac-Nle-c(Asp-Pro-dNal(2')-dLys-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:99);

[0626] Ac-Nle-c(Asp-Pro-dNal(2')-dArg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 100);

[0627] Ac-Nle-c(Asp-Pro-dNal(2')-Orn-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:101);

[0628] Ac-Nle-c(Asp-Pro-dNal(2')-dOrn-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:102);

[0629] Ac-Nle-c(Asp-Pro-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:103);

[0630] Ac-Nle-c(Asp-Pro-dNal(2')-Ala-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:104);

[0631] Ac-Nle-c(Asp-Pro-dNal(2')-Gly-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:105);

[0632] Ac-Nle-c(Asp-Pro-dNal(2')-Asp-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:106);

[0633] Ac-Nle-c(Asp-Pro-dNal(2')-Glu-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:107);

[0634] Ac-Nle-c(Asp-Pro-dNal(2')-dHis-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:108);

[0635] Ac-Nle-c(Asp-Pro-dNal(2')-dAla-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:109);

[0636] Ac-Nle-c(Asp-Pro-dNal(2')-dAsp-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:110); and

[0637] Ac-Nle-c(Asp-Pro-dNal(2')-dGlu-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:111),

[0638] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[0639] In some embodiments of the sequence of equation (I), R 6 For Trp. Alternatively, in some embodiments, R 6 The amino acid is absent or is an amino acid other than Trp. In some embodiments, the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Lys)-dVal-dPro-NH2(SEQ ID NO:112);

[0640] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Nal(1')-Lys)-dVal-dPro-NH2 (SEQ ID NO: 113);

[0641] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Aia-Lys)-dVal-dPro-NH2 (SEQ ID NO: 114);

[0642] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Phe-Lys)-dVal-dPro-NH2 (SEQ ID NO: 115);

[0643] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Tyr-Lys)-dVal-dPro-NH2 (SEQ ID NO: 116);

[0644] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-His-Lys)-dVal-dPro-NH2 (SEQ ID NO: 117);

[0645] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Ala-Lys)-dVal-dPro-NH2 (SEQ ID NO: 118);

[0646] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dNal(1')-Lys)-dVal-dPro-NH2 (SEQ ID NO: 119);

[0647] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dPhe-Lys)-dVal-dPro-NH2 (SEQ ID NO: 120);

[0648] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dNal(2')-Lys)-dVal-dPro-NH2 (SEQ ID NO: 121);

[0649] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dTyr-Lys)-dVal-dPro-NH2 (SEQ ID NO: 122);

[0650] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dHis-Lys)-dVal-dPro-NH2 (SEQ ID NO: 123); and

[0651] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dAla-Lys)-dVal-dPro-NH2 (SEQ ID NO: 124),

[0652] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[0653] In some embodiments of the sequence of equation (I), R 4 For dNal(2'). Alternatively, in some embodiments, R 4 Amino acids other than dNal(2'). For example, in some embodiments, when R 4 When R is an amino acid other than dNal(2'), 4 For Bip. In some embodiments, the sequence of formula (I) is Ac-Nle-c(Asp-Pro-Bip-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:125), where c represents through R 2 and R 7 Cyclation via lactam bonds.

[0654] In some embodiments of the sequence of equation (I), Y 1 For dVal and Y 2For dPro. Alternatively, in some embodiments, Y 1 It consists of amino acids other than dVal, and Y 2 These are amino acids other than dPro. In some embodiments, Y 1 For dVal and Y 2 These are amino acids other than dPro. In some embodiments, Y 1 It consists of amino acids other than dVal and Y 2 For dPro.

[0655] In some embodiments, Y 1 For dVal, Y 2 It is dPro, and the C-terminus is modified with NH2. In some embodiments, Y 1 Y consists of amino acids other than dVal. 2 It consists of amino acids other than dPro, and its C-terminus is modified with NH2. In some embodiments, Y 1 For dVal, Y 2 It consists of amino acids other than dPro, and its C-terminus is modified with NH2. In some embodiments, Y 1 Y consists of amino acids other than dVal. 2 It is dPro, and the C-terminus is modified with NH2. In some embodiments, Y 1 For dVal, Y 2 It is dPro, and the C-terminus is not modified.

[0656] In the embodiment of formula (I), when Y 1 When Y is an amino acid other than dVal, then 1 Selected from dPro, Val, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, Lys, dLys, and dTle. In the embodiment of formula (I), when Y 2 When Y is an amino acid other than dPro, then 2 Alternatively, it may be selected from dVal, Val, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, and dTle. In some embodiments, the sequence of formula (I) is selected from the group consisting of:

[0657] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-Pro-NH2 (SEQ ID NO: 126);

[0658] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-OH(SEQ ID NO:127);

[0659] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-OH(SEQ ID NO:128);

[0660] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO:129);

[0661] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dHyp-NH2(SEQ ID NO:130);

[0662] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-Hyp-NH2(SEQ ID NO:131);

[0663] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-dHyp-NH2(SEQ ID NO:132);

[0664] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-dVal-NH2(SEQ ID NO:133);

[0665] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-dVal-NH2(SEQ ID NO:134);

[0666] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-Val-NH2(SEQ ID NO:135);

[0667] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-Val-NH2(SEQ ID NO:136);

[0668] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-NH2(SEQ ID NO:137);

[0669] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dPro-NH2(SEQ ID NO:138);

[0670] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-NH2(SEQ ID NO:139);

[0671] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-NH2(SEQ ID NO:140);

[0672] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-NH2(SEQ ID NO:141);

[0673] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Pro-NH2(SEQ ID NO:142);

[0674] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Ala-NH2(SEQ ID NO:143);

[0675] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAla-NH2(SEQ ID NO:144);

[0676] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-NH2(SEQ ID NO:145);

[0677] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-NH2(SEQ ID NO:146);

[0678] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAla-dAla-NH2(SEQ ID NO:147);

[0679] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Ala-Ala-NH2(SEQ ID NO:148);

[0680] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Gly-Gly-NH2(SEQ ID NO:149);

[0681] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Asp-NH2(SEQ ID NO:150);

[0682] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Arg-NH2(SEQ ID NO:151);

[0683] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Asn-NH2(SEQ ID NO:152);

[0684] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dAsp-NH2(SEQ ID NO:153);

[0685] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dArg-NH2(SEQ ID NO:154);

[0686] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dAsn-NH2(SEQ ID NO:155);

[0687] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asp-dPro-NH2(SEQ ID NO:156);

[0688] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dPro-NH2(SEQ ID NO:157);

[0689] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asn-dPro-NH2(SEQ ID NO:158);

[0690] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsp-dPro-NH2(SEQ ID NO:159);

[0691] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dPro-NH2(SEQ ID NO:160);

[0692] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsn-dPro-NH2(SEQ ID NO:161);

[0693] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asp-NH2(SEQ ID NO:162);

[0694] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-NH2(SEQ ID NO:163);

[0695] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asn-NH2(SEQ ID NO:164);

[0696] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsp-NH2(SEQ ID NO:165);

[0697] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-NH2(SEQ ID NO:166);

[0698] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsn-NH2(SEQ ID NO:167);

[0699] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-Pro-Val-NH2(SEQ ID NO:168);

[0700] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-dPro-dVal-NH2(SEQ ID NO:169);

[0701] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLys-dPro-dVal-NH2(SEQ ID NO:170);

[0702] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-dPro-NH2(SEQ ID NO:171);

[0703] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLys-dPro-NH2(SEQ ID NO:172);

[0704] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-Val-Pro-NH2(SEQ ID NO:173);

[0705] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-dVal-dPro-NH2(SEQ ID NO:174);

[0706] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLys-dVal-dPro-NH2(SEQ ID NO:175);

[0707] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-Pro-Val-NH2(SEQ ID NO:176);

[0708] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dPro-dVal-NH2(SEQ ID NO:177);

[0709] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dPro-dVal-NH2(SEQ ID NO:178);

[0710] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-Val-Pro-NH2(SEQ ID NO:179);

[0711] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dVal-dPro-NH2 (SEQ ID NO:180);

[0712] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dVal-dPro-NH2 (SEQ ID NO:181);

[0713] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dVal-dPro-NH2 (SEQ ID NO:182);

[0714] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dPro-NH2 (SEQ ID NO:183);

[0715] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dVal-NH2 (SEQ ID NO:184);

[0716] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dTle-NH2 (SEQ ID NO:185);

[0717] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dTle-dPro-NH2 (SEQ ID NO:186);

[0718] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dTle-dVal-NH2 (SEQ ID NO:187);

[0719] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dTle-NH2 (SEQ ID NO:188); and

[0720] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dTle-NH2 (SEQ ID NO:189),

[0721] where c represents via R 2 and R 7Cyclation via lactam bonds.

[0722] In some embodiments of the sequence of equation (I), when Y 3 Existence and Y 4-8 If it does not exist, then Y 1 Y 2 and Y 3 Each of these is independently selected from dVal and dPro. In some embodiments of the sequence of equation (I), when Y 3 and Y 4 Existence and Y 5-8 If it does not exist, then Y 1 Y 2 Y 3 and Y 4 Each of these is independently selected from dVal and dPro. In some embodiments of the sequence of equation (I), when Y 3 To Y 5 Existence and Y 6-8 If it does not exist, then Y 1 To Y 5 Either dVal or dPro can be chosen independently. In some embodiments of the sequence of equation (I), when Y 3 To Y 6 Existence and Y 7-8 If it does not exist, then Y 1 To Y 6 Either dVal or dPro can be chosen independently. In some embodiments of the sequence of equation (I), when Y 3 To Y 7 Existence and Y 8 If it does not exist, then Y 1 To Y 7 Each of these is independently selected from dVal and dPro. In some embodiments of the sequence of equation (I), when Y 3 To Y 8 If it exists, then Y 1 To Y 8 Each of these is independently selected from dVal and dPro. In some embodiments, the sequence of equation (I) is selected from the group consisting of:

[0723] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dPro-NH2 (SEQ ID NO: 190);

[0724] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-dPro-NH2 (SEQ ID NO: 191);

[0725] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dVal-dPro-NH2 (SEQ IDNO: 192);

[0726] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 193); and

[0727] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dVal-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 194),

[0728] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[0729] In some embodiments of the sequence of equation (I), X 1 It exists and is acetylated leucine, and R 1 It is present and is leucine. In some embodiments, X... 2 It is present and is leucine. In some embodiments, X... 3 It is present and is leucine. In some embodiments, the sequence of formula (I) is selected from the group consisting of:

[0730] Ac-Nle-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 195);

[0731] Ac-Nle-Nle-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 196); and

[0732] Ac-Nle-Nle-Nle-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 197),

[0733] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[0734] As described above, some non-natural melanocortin analogs containing the sequence of formula (I) can bind to melanocortin 3 and melanocortin 4 receptors with the same or generally similar affinity. Other non-natural melanocortin analogs containing the sequence of formula (I) can bind to melanocortin 3 receptors with a greater affinity than melanocortin 4 receptors. In some embodiments, when the non-natural melanocortin analogs of the present invention bind to melanocortin 3 receptors with a greater affinity than melanocortin 4 receptors, the sequence of formula (I) is selected from the group consisting of:

[0735] Ac-Nle-c(Asp-Pro-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 198);

[0736] Ac-Nle-c(Asp-Trp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 199);

[0737] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dTrp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 200);

[0738] c(CO-cis-CH=CH-CO-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ IDNO: 201);

[0739] Ac-Nle-c(Asp-β-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 202);

[0740] Ac-Nle-c(Asp-Mamb-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 203);

[0741] Ac-Nle-c(Asp-Acpc-dNal(2')Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 204);

[0742] Ac-c(Cys-Arg-dPhe-Cys)-Trp-dVal-dPro-NH2 (SEQ ID NO: 205);

[0743] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Trp-NH2 (SEQ ID NO: 206);

[0744] Ac-Nle-c(Asp-Aba-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 207);

[0745] Ac-Nle-c(Asp-Aia-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:208); and

[0746] Ac-Nle-c(Asp-Ata-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 209),

[0747] Where c represents through R 1 Or R 2 and R 7 Or R 8 via lactam cyclization or through R 2 and R 5 Cycling via disulfide bonds.

[0748] Some non-natural melanocortin analogs containing the sequence of formula (I) can bind to the melanocortin 4 receptor with a greater affinity than the melanocortin 3 receptor. In some embodiments, when a non-natural melanocortin analog binds to the melanocortin 4 receptor with a greater affinity than the melanocortin 3 receptor, the sequence of formula (I) is selected from the group consisting of:

[0749] Ac-Nle-c(Asp-Aic-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 210);

[0750] Ac-Nle-c(Asp-Cpe-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 211);

[0751] Ac-Nle-c(Asp-Che-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 212);

[0752] Ac-Nle-c(Asp-Oic-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:213);

[0753] Ac-Nle-c(Asp-Ioc-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:214);

[0754] Ac-Nle-c(Asp-Tic-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:215);

[0755] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO:216);

[0756] Ac-Nle-c(Asp-His-dNal(2')-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:217);

[0757] Ac-Nle-c(Asp-His-dNal(2')-trans-Pro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:218);

[0758] Ac-Nle-c(Asp-His-dNal(2')-cis-Pro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:219);

[0759] Ac-Nle-c(Asp-Pro-dNal(2')-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:220);

[0760] Ac-Nle-c(Asp-Pro-dNal(2')-trans-Pro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:221);

[0761] Ac-Nle-c(Asp-Pro-dNal(2')-cis-Pro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:222);

[0762] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Aba-Lys)-dVal-dPro-NH2 (SEQ ID NO:223);

[0763] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Ata-Lys)-dVal-dPro-NH2 (SEQ ID NO:224);

[0764] Ac-Nle-c(Asp-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:225);

[0765] Ac-Nle-c(Asp-Glu-dNal(2')-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO:226);

[0766] Ac-Nle-c(Asp-Pro-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:227);

[0767] Ac-Nle-c(Asp-Pro-Glu-dNal(2')-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO:228);

[0768] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO:229);

[0769] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO:230);

[0770] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO:231);

[0771] Ac-Glu-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO:232);

[0772] and

[0773] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dPro-dLys-dAsp-NH2(SEQ IDNO:233),

[0774] Where c represents through R 1 Or R 2 and R 7 Cyclation via lactam bonds.

[0775] In some embodiments of the sequence of equation (I), when X 1 Existence and X 2 and X 3 When it does not exist, the sequence of equation (I) is passed through R. 1 With R 5-8 Cycling of either the lactam bond or disulfide bond between them. In some embodiments, when X 1 Existence and X 2 and X 3 When it does not exist, the sequence of equation (I) is passed through R. 1 With R 6 Cyclation of the lactam bond between them. In some embodiments, when X 1 Existence and X 2 and X 3 When it does not exist, the sequence of equation (I) is passed through R. 1 With R 7 Cyclation of lactam bonds between them. In some embodiments, Y 1 and Y 2 They exist and are respectively dVal and dPro, and Y 3 To Y 8 It does not exist. In some embodiments, Y 1 To Y 8 No. In some embodiments, the sequence of equation (I) is selected from the group consisting of the following:

[0776] Ac-Nle-c(Asp-Glu-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 234);

[0777] Ac-Nle-c(Asp-Glu-His-dNal(2')-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ IDNO: 235);

[0778] Ac-Nle-c(Asp-dAla-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:236);

[0779] Ac-Arg-c(Asp-dAla-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:237);

[0780] Ac-Arg-c(Asp-dAla-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:238);

[0781] Ac-Arg-c(Cys-dAla-His-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:239);

[0782] Ac-dArg-c(Asp-dAla-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:240);

[0783] Ac-Arg-c(Asp-dAla-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:241);

[0784] Ac-dArg-c(Asp-dAla-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:242);

[0785] Ac-Nle-c(Asp-Ala-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:243);

[0786] Ac-Arg-c(Asp-Ala-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:244);

[0787] Ac-dArg-c(Asp-Ala-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:245);

[0788] Ac-Nle-c(Asp-Trp-Arg-dNal(2')-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 246);

[0789] Ac-Nle-c(Asp-Pro-Trp-dNal(2')-Lys)-dVal-dPro-NH2 (SEQ ID NO: 247);

[0790] Ac-Nle-c(Asp-Pro-Trp-Arg-dNal(2')-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 248);

[0791] Ac-Nle-c(Asp-Pro-Trp-Arg-dNal(2')-Lys)-dVal-dPro-NH2 (SEQ ID NO: 249);

[0792] Ac-Nle-c(Lys-Trp-Arg-dNal(2')-Pro-Asp)-dVal-dPro-NH2 (SEQ ID NO: 250);

[0793] Ac-Arg-c(Cys-dAla-His-dNal(2')-Arg-Trp-Cys)-NH2 (SEQ ID NO: 251);

[0794] Ac-Arg-c(Asp-dAla-His-dNal(2')-Arg-Trp-Lys)-NH2 (SEQ ID NO: 252);

[0795] Ac-Arg-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 253); and

[0796] Ac-Arg-c(Asp-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:254),

[0797] Where c represents through R 1 and R 5-8 One of them is cyclized via a lactam bond or a disulfide bond.

[0798] In some embodiments of the sequence of equation (I), when X 1 and X 2 Existence and X 3 It does not exist; the sequence of equation (I) is passed through R.1 With R 6 Cyclation of lactam bonds between them. In such embodiments, X 1 and X 2 Each is independently selected from dVal and dPro. In some embodiments, the sequence of formula (I) is selected from the group consisting of:

[0799] Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2')-Pro-Lys)-Nle-NH2 (SEQ ID NO: 255);

[0800] Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2')-Pro-Asp)-Nle-NH2 (SEQ ID NO: 256);

[0801] Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2')-Pro-Lys)-Nle-Nle-NH2 (SEQ ID NO: 257);

[0802] Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2')-Pro-Asp)-Nle-Nle-NH2 (SEQ ID NO: 258);

[0803] Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2')-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 259); and

[0804] Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2')-Pro-Asp)-dVal-dPro-NH2(SEQ ID NO:260), where c represents the result of passing through R 2 and R 7 Cyclation via lactam bonds.

[0805] In some embodiments of the sequence of equation (I), R 1 For Nle, and X 1 and X 2 One or more of them exist. In some embodiments, R 1 For Nle, X 1 Exists, and X 2 It does not exist. In some embodiments, R 1 For Nle, and X 1 and X 2 Yes. In some embodiments, the sequence of equation (I) is:

[0806] Ac-dVal-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:261); or

[0807] Tyr-Val-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:262), where c represents the expression via R 2 and R 7 Cyclation via lactam bonds.

[0808] In some embodiments of the sequence of equation (I), R 1 For Ac-Glu. In some embodiments, R 1 For Ac-Glu, R 2 For Asp, R 3 For Glu, His, or Arg, R 4 For dNal(2'), R 5 For Arg, R 6 For Trp, and R 7 For Lys. In some embodiments, the sequence of equation (I) is selected from the group consisting of:

[0809] Ac-Glu-c(Asp-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 263);

[0810] Ac-Glu-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 264); and

[0811] Ac-Glu-c(Asp-Arg-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 265),

[0812] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[0813] In some embodiments of the sequence of equation (I), R 5 For His. In some embodiments, when R 5 When it is His, then R 3 For His and the sequence of equation (I) through R 1 Or R 2 and R7 Via lactam cyclization. In some embodiments, X 1 If it is Ac-Arg or does not exist, R 1 If it is Ac-Nle, Asp, or does not exist, R 2 For Asp or Pro, R 3 For His, R 4 For dNal(2'), R 5 For His, R 6 For Trp, and R 7 For Lys or Dap. In some embodiments, the sequence of equation (I) is selected from the group consisting of:

[0814] Ac-Nle-c(Asp-Pro-His-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 266);

[0815] Ac-Nle-c(Asp-His-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 267);

[0816] Ac-Arg-c(Asp-Pro-His-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 268);

[0817] Ac-Arg-c(Asp-His-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 269);

[0818] Ac-Nle-c(Asp-Pro-His-dNal(2')-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 270);

[0819] Ac-Nle-c(Asp-His-dNal(2')-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 271);

[0820] Ac-Nle-c(Asp-Pro-His-dNal(2')-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 272);

[0821] Ac-Nle-c(Asp-His-dNal(2')-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 273);

[0822] Ac-Arg-c(Asp-Pro-His-dNal(2')-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 274);

[0823] Ac-Arg-c(Asp-His-dNal(2')-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 275);

[0824] Ac-Arg-c(Asp-Pro-His-dNal(2')-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 276);

[0825] Ac-Arg-c(Asp-His-dNal(2')-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 277);

[0826] Ac-Nle-c(Asp-Pro-His-dNal(2')-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 278);

[0827] Ac-Nle-c(Asp-His-dNal(2')-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 279);

[0828] Ac-Arg-c(Asp-Pro-His-dNal(2')-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 280);

[0829] Ac-Arg-c(Asp-His-dNal(2')-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 281);

[0830] Where c represents through R 1 Or R 2 and R 7 Cyclation via lactam bonds.

[0831] In some embodiments of the sequence of equation (I), R 1 For Ac-Nle, R 2For Asp and dAsp, R 3 For Pro or His, R 4 For dNal(2'), R 5 For Arg, R 6 For Trp, and R 7 For Lys and dLys. In such embodiments, Y... 1 Y 2 and Y 3 Variation. In some embodiments, the sequence of equation (I) is selected from the group consisting of the following:

[0832] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dThr-dPro-dThr-NH2 (SEQ ID NO: 282);

[0833] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 283);

[0834] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dThr-dPro-dThr (SEQ ID NO: 284);

[0835] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dThr-dPro-dThr (SEQ ID NO: 285);

[0836] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 286);

[0837] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 287);

[0838] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 288);

[0839] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 289);

[0840] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:290);

[0841] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:291);

[0842] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH2(SEQ ID NO:292);

[0843] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH2(SEQ ID NO:293);

[0844] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Val-NH2(SEQ ID NO:294);

[0845] Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β 3 Pro-β 2 Val-NH2(SEQ ID NO:295);

[0846] Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β 3 Pro-β 3 Val-NH2(SEQ ID NO:296);

[0847] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Val-NH2(SEQ ID NO:297);

[0848] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Val-NH2(SEQ ID NO:298);

[0849] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Val-NH2(SEQ ID NO:299);

[0850] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Val-β-Pro-NH2(SEQ ID NO:300);

[0851] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β 2 Val-β 3 Pro-NH2(SEQ ID NO:301)?

[0852] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β 3 Val-β 3 Pro-NH2(SEQ ID NO:302)?

[0853] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Val-β-Pro-NH2(SEQ ID NO:303);

[0854] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Val-β-Pro-NH2(SEQ ID NO:304);

[0855] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Val-β-Pro-NH2(SEQ ID NO:305);

[0856] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Pro-NH2(SEQ ID NO:306);

[0857] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β 3 Pro-β 3 Pro-NH2(SEQ ID NO:307)?

[0858] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Pro-NH2(SEQ ID NO:308);

[0859] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Pro-NH2 (SEQ ID NO:309);

[0860] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Pro-NH2 (SEQ ID NO:310);

[0861] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Val-β-Val-NH2 (SEQ ID NO:311);

[0862] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Val-β-Val-NH2 (SEQ ID NO:312);

[0863] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Val-β-Val-NH2 (SEQ ID NO:313);

[0864] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Val-β-Val-NH2 (SEQ ID NO:314);

[0865] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Val-NH2 (SEQ ID NO:315);

[0866] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Val-NH2 (SEQ ID NO:316);

[0867] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Val-NH2 (SEQ ID NO:317);

[0868] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Val-NH2 (SEQ ID NO:318);

[0869] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Pro-NH2 (SEQ ID NO:319);

[0870] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Pro-NH2 (SEQ ID NO:320);

[0871] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Pro-NH2 (SEQ ID NO:321);

[0872] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Pro-NH2 (SEQ ID NO:322);

[0873] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Thr-β-Pro-β-Thr (SEQ ID NO:323);

[0874] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Thr-β-Pro-β-Thr (SEQ ID NO:324);

[0875] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Thr-β-Pro-β-Thr (SEQ ID NO:325);

[0876] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Thr-β-Pro-β-Thr (SEQ ID NO:326);

[0877] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO:327);

[0878] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO:328);

[0879] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dPro-dAla-NH2(SEQ ID NO:329);

[0880] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dAla-NH2(SEQ ID NO:330);

[0881] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAla-dPro-NH2(SEQ ID NO:331);

[0882] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dAla-dPro-NH2(SEQ ID NO:332);

[0883] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dAla-dPro-NH2(SEQ ID NO:333);

[0884] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dAla-dPro-NH2(SEQ ID NO:334);

[0885] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Ala-NH2(SEQ ID NO:335);

[0886] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Ala-NH2(SEQ ID NO:336);

[0887] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Ala-NH2(SEQ ID NO:337);

[0888] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Ala-NH2(SEQ ID NO:338);

[0889] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Ala-β-Pro-NH2 (SEQ ID NO:339);

[0890] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Ala-β-Pro-NH2 (SEQ ID NO:340);

[0891] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Ala-β-Pro-NH2 (SEQ ID NO:341);

[0892] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Ala-β-Pro-NH2 (SEQ ID NO:342);

[0893] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Val-β-Ala-NH2 (SEQ ID NO:343);

[0894] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Val-β-Ala-NH2 (SEQ ID NO:344);

[0895] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Val-β-Ala-NH2 (SEQ ID NO:345);

[0896] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Val-β-Ala-NH2 (SEQ ID NO:346);

[0897] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO:347);

[0898] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO:348);

[0899] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO:349);

[0900] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO:350)

[0901] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO:351);

[0902] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO:352);

[0903] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO:353);

[0904] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO:354);

[0905] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO:355);

[0906] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO:356);

[0907] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO:357);

[0908] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO:358);

[0909] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Leu-NH2(SEQ ID NO:359);

[0910] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Leu-NH2(SEQ ID NO:360);

[0911] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Leu-NH2(SEQ ID NO:361);

[0912] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Leu-NH2(SEQ ID NO:362);

[0913] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Leu-β-Pro-NH2(SEQ ID NO:363);

[0914] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Leu-β-Pro-NH2(SEQ ID NO:364);

[0915] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Leu-β-Pro-NH2(SEQ ID NO:365);

[0916] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Leu-β-Pro-NH2(SEQ ID NO:366);

[0917] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Val-β-Leu-NH2(SEQ ID NO:367);

[0918] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Val-β-Leu-NH2(SEQ ID NO:368);

[0919] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Val-β-Leu-NH2 (SEQ ID NO: 369);

[0920] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Val-β-Leu-NH2 (SEQ ID NO: 370);

[0921] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 371);

[0922] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 372);

[0923] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2(SEQID NO:373); and

[0924] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 374),

[0925] Where c represents through R 1 and R 7 Cyclation via lactam bonds.

[0926] Alternatively, in some embodiments, the non-naturally occurring melanocortin analogue comprises a sequence selected from the group consisting of:

[0927] Ac-Nle-c(Asp-Pro-dPhe-Arg-dTrp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 375);

[0928] Ac-Nle-c(Asp-His-Arg-p(I)dPhe-Arg-Tic-Lys)-dVal-dPro-NH2 (SEQ ID NO: 376);

[0929] Ac-Nle-c(Asp-His-Arg-dBip-Arg-Tic-Lys)-dVal-dPro-NH2(SEQ ID NO:377);

[0930] Ac-Nle-c(Asp-Pro-Arg-p(I)dPhe-Arg-Tic-Lys)-dVal-dPro-NH2(SEQ ID NO:378);

[0931] Ac-Nle-c(Asp-Pro-Arg-dBip-Arg-Tic-Lys)-dVal-dPro-NH2(SEQ ID NO:379);

[0932] Ac-Nle-c(Asp-Arg-Pro-p(I)dPhe-Arg-Tic-Lys)-dVal-dPro-NH2(SEQ ID NO:380);

[0933] Ac-Nle-c(Asp-Arg-Pro-dBip-Arg-Tic-Lys)-dVal-dPro-NH2(SEQ ID NO:381);

[0934] Ac-Nle-c(Asp-Aba-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:382);

[0935] Ac-Nle-c(Asp-Aia-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:383);

[0936] Ac-Nle-c(Asp-Ata-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:384);

[0937] Ac-Nle-c(Asp-Aba-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:385);

[0938] Ac-Nle-c(Asp-Aia-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:386);

[0939] Ac-Nle-c(Asp-Ata-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:387);

[0940] Ac-Nle-c(Asp-Atc-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:388);

[0941] Ac-Nle-c(Asp-APC-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:389);

[0942] Ac-Nle-c(Asp-APPC-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:390);

[0943] Ac-Nle-c(Asp-Pro-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:391);

[0944] Ac-Nle-c(Asp-Pro-p(I)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:392);

[0945] Ac-Nle-c(Asp-Pro-p(Br)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:393);

[0946] Ac-Nle-c(Asp-Pro-p(F)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:394);

[0947] Ac-Nle-c(Asp-Pro-p(CF3)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:395);

[0948] Ac-Nle-c(Asp-His-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:396);

[0949] Ac-Nle-c(Asp-His-p(I)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:397);

[0950] Ac-Nle-c(Asp-His-p(Br)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:398);

[0951] Ac-Nle-c(Asp-His-p(F)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:399);

[0952] Ac-Nle-c(Asp-His-p(CF3)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:400);

[0953] Ac-Nle-c(Asp-Pro-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:401);

[0954] Ac-Nle-c(Asp-Trp-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:402);

[0955] Ac-Nle-c(Asp-His-dPhe-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:403);

[0956] Ac-Nle-c(Asp-His-dPhe- trans-Pro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:404);

[0957] Ac-Nle-c(Asp-His-dPhe- cis-Pro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:405);

[0958] Ac-Nle-c(Asp-Pro-dPhe-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:406);

[0959] Ac-Nle-c(Asp-Pro-dPhe-transPro(guan)-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:407);

[0960] Ac-Nle-c(Asp-Pro-dPhe-cisPro(guan)-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:408);

[0961] Ac-Nle-c(Asp-Pro-dPhe-Arg-Aia-Lys)-dVal-dPro-NH2 (SEQ ID NO: 409);

[0962] Ac-Nle-c(Asp-Pro-dPhe-Arg-Aba-Lys)-dVal-dPro-NH2 (SEQ ID NO: 410);

[0963] Ac-Nle-c(Asp-Pro-dPhe-Arg-Ata-Lys)-dVal-dPro-NH2 (SEQ ID NO: 411);

[0964] Ac-Nle-c(Asp-Pro-p(CF3)dPhe-Arg-Aia-Lys)-dVal-dPro-NH2 (SEQ ID NO: 412);

[0965] Ac-Nle-c(Asp-Pro-p(CF3)dPhe-Arg-Aba-Lys)-dVal-dPro-NH2 (SEQ ID NO: 413);

[0966] Ac-Nle-c(Asp-Pro-p(CF3)dPhe-Arg-Ata-Lys)-dVal-dPro-NH2(SEQ ID NO:414); and

[0967] Ac-Arg-c(Asp-dAla-His-dPhe-Arg-Trp-Lys)-NH2 (SEQ ID NO:415),

[0968] Where c represents through R 1 and R 7 Or R 8 Cyclation via lactam bonds.

[0969] Alternatively, in some embodiments, the non-naturally occurring melanocortin analogue comprises a sequence selected from the group consisting of:

[0970] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dThr-dPro-dThr(SEQ ID NO:416);

[0971] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dThr-dPro-dThr(SEQ ID NO:417);

[0972] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dThr-dPro-dThr(SEQ ID NO:418);

[0973] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dlys)-dThr-dPro-dThr(SEQ ID NO:419);

[0974] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO:420);

[0975] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dPro-dVal-NH2(SEQ ID NO:421);

[0976] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO:422);

[0977] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO:423);

[0978] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:424);

[0979] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:425);

[0980] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dVal-dPro-NH2(SEQ ID NO:426);

[0981] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH2(SEQ ID NO:427);

[0982] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βPro-βVal-NH2(SEQ ID NO:428);

[0983] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βPro-βVal-NH2(SEQ ID NO:429);

[0984] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-βPro-βVal-NH2(SEQ ID NO:430);

[0985] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-βPro-βVal-NH2(SEQ ID NO:431);

[0986] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βVal-βPro-NH2(SEQ ID NO:432);

[0987] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βVal-βPro-NH2(SEQ ID NO:433);

[0988] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-βVal-βPro-NH2(SEQ ID NO:434);

[0989] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-βVal-βPro-NH2(SEQ ID NO:435);

[0990] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βPro-βPro-NH2(SEQ ID NO:436);

[0991] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βPro-βPro-NH2(SEQ ID NO:437);

[0992] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-βPro-βPro-NH2 (SEQ ID NO:438);

[0993] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-βPro-βPro-NH2 (SEQ ID NO:439);

[0994] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βVal-βVal-NH2 (SEQ ID NO:440);

[0995] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βVal-βVal-NH2 (SEQ ID NO:441);

[0996] Ac-Nle-c(dAsp-Pro-Phe-Arg-Trp-dLys)-βVal-βVal-NH2 (SEQ ID NO:442);

[0997] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-βVal-βVal-NH2 (SEQ ID NO:443);

[0998] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO:444);

[0999] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO:445);

[1000] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO:446);

[1001] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO:447);

[1002] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βPro-NH2 (SEQ ID NO:448);

[1003] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βPro-NH2 (SEQ ID NO:449);

[1004] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-(3-methyl)-βVal-βPro-NH2 (SEQ ID NO:450);

[1005] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-βVal-βPro-NH2 (SEQ ID NO:451);

[1006] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βThr-βPro-βThr (SEQ ID NO:452);

[1007] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βThr-βPro-βThr (SEQ ID NO:453);

[1008] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-βThr-βPro-βThr (SEQ ID NO:454);

[1009] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-βThr-βPro-βThr (SEQ ID NO:455);

[1010] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO:456);

[1011] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO:457);

[1012] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dPro-dAla-NH2(SEQ ID NO:458);

[1013] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dPro-dAla-NH2(SEQ ID NO:459);

[1014] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dAla-dPro-NH2(SEQ ID NO:460);

[1015] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dAla-dPro-NH2(SEQ ID NO:461);

[1016] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dAla-dPro-NH2(SEQ ID NO:462);

[1017] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dAla-dPro-NH2(SEQ ID NO:463);

[1018] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βPro-βAla-NH2(SEQ ID NO:464);

[1019] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βPro-βAla-NH2(SEQ ID NO:465);

[1020] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-βPro-βAla-NH2(SEQ ID NO:466);

[1021] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-βPro-βAla-NH2(SEQ ID NO:467);

[1022] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βAla-βPro-NH2(SEQ ID NO:468);

[1023] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βAla-βPro-NH2(SEQ ID NO:469);

[1024] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-βAla-βPro-NH2(SEQ ID NO:470);

[1025] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-βAla-βPro-NH2(SEQ ID NO:471);

[1026] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βVal-βAla-NH2(SEQ ID NO:472);

[1027] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βVal-βAla-NH2(SEQ ID NO:473);

[1028] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-βVal-βAla-NH2(SEQ ID NO:474);

[1029] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-βVal-βAla-NH2(SEQ ID NO:475);

[1030] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βAla-NH2(SEQ ID NO:476);

[1031] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βAla-NH2(SEQ ID NO:477);

[1032] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-(3-methyl)-βVal-βAla-NH2(SEQ ID NO:478);

[1033] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO:479);

[1034] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO:480);

[1035] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO:481);

[1036] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dPro-dLeu-NH2 (SEQ ID NO:482);

[1037] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO:483);

[1038] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO:484);

[1039] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO:485);

[1040] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO:486);

[1041] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO:487);

[1042] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-β-Pro-β-Leu-NH2 (SEQ ID NO:488);

[1043] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-β-Pro-β-Leu-NH2 (SEQ ID NO:489);

[1044] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-β-Pro-β-Leu-NH2(SEQ ID NO:490);

[1045] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Leu-NH2(SEQ ID NO:491);

[1046] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-β-Leu-β-Pro-NH2(SEQ ID NO:492);

[1047] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-β-Leu-β-Pro-NH2(SEQ ID NO:493);

[1048] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-β-Leu-β-Pro-NH2(SEQ ID NO:494);

[1049] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-β-Leu-β-Pro-NH2(SEQ ID NO:495);

[1050] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-β-Val-β-Leu-NH2(SEQ ID NO:496);

[1051] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-β-Val-β-Leu-NH2(SEQ ID NO:497);

[1052] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-β-Val-β-Leu-NH2(SEQ ID NO:498);

[1053] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-β-Val-β-Leu-NH2(SEQ ID NO:499);

[1054] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ IDNO: 500);

[1055] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ IDNO: 501);

[1056] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 502); and

[1057] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ IDNO: 503),

[1058] Where c represents through R 1 and R 7 Cyclation via lactam bonds.

[1059] In some embodiments, the non-naturally occurring melanocortin analogue is a melanocortin receptor antagonist, such as a melanocortin 3 receptor and / or melanocortin 4 receptor antagonist. In some embodiments, the non-naturally occurring melanocortin analogue is a melanocortin receptor agonist, such as a melanocortin 1 receptor, melanocortin 3 receptor, melanocortin 4 receptor, and / or melanocortin 5 receptor agonist. For example, in some embodiments, the melanocortin analogue has agonist activity against melanocortin 3 and / or melanocortin 4 receptors, as well as against melanocortin 1 and melanocortin 5 receptors. In other embodiments, the melanocortin analogue has antagonist activity against melanocortin 3 and / or melanocortin 4 receptors, and agonist activity against melanocortin 1 and melanocortin 5 receptors.

[1060] In some embodiments, non-naturally occurring melanocortin analogs include any of the techniques of the present invention. In some embodiments, non-naturally occurring melanocortin analogs comprise any of the sequences of SEQ ID NO:2 to 374. In some embodiments, non-naturally occurring melanocortin antagonist analogs comprise any of the sequences of SEQ ID NO:2 to 281. In some embodiments, non-naturally occurring melanocortin antagonist analogs comprise any of the following sequences: SEQ ID NO:3, 20, 29 to 32, 67 to 70, 99 to 102, 127 to 130, 159, 163 to 166, 187 to 190, 391, 394, 396, 398, and 399. In some embodiments, non-naturally occurring melanocortin antagonist analogues comprise any of the following sequences: SEQ ID NO: 10, 14, 33 to 39, 82 to 96, 108 to 111, 119 to 124, 128, 182 to 189, 212 to 281, 394 and 399.

[1061] In some embodiments, the non-naturally occurring melanocortin analogue comprises the sequence of SEQ ID NO:3 (“TCMCB07”). The structure of TCMCB07 (“B07”), comprising Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2, is shown below:

[1062]

[1063] Preparations

[1064] Compositions containing carriers and / or excipients of the present invention facilitate the delivery of non-natural melanocortin analogs in any of the embodiments to subjects.

[1065] In some embodiments, the non-natural melanocortin analogue is present in the composition.

[1066] In some embodiments, the non-naturally occurring melanocortin analogue is present in the composition at a concentration of 0.1 mg / mL to 500 mg / mL relative to the total volume of the composition. For example, the non-naturally occurring melanocortin analogue is present in the composition at concentrations of 0.1 mg / mL to 500 mg / mL, 0.5 mg / mL to 250 mg / mL, 1 mg / mL to 100 mg / mL, 2.5 mg / mL to 50 mg / mL, or 5 mg / mL to 25 mg / mL relative to the total volume of the composition. In some embodiments, the non-naturally occurring melanocortin analogue is present in the composition at a concentration of about 50 mg / mL relative to the total volume of the composition.

[1067] In some embodiments, the non-naturally occurring melanocortin analogue comprises TCMCB07, and the non-naturally occurring melanocortin analogue is present in the composition at a concentration of 5 mg / mL to 100 mg / mL relative to the total volume of the composition. For example, the non-naturally occurring melanocortin analogue comprising TCMCB07 is present in the composition at concentrations of 5 mg / mL to 100 mg / mL, 10 mg / mL to 75 mg / mL, 15 mg / mL to 50 mg / mL, 20 mg / mL to 40 mg / mL, or 25 mg / mL to 30 mg / mL relative to the total volume of the composition. In some embodiments, the non-naturally occurring melanocortin analogue comprising TCMCB07 is present in the composition at a concentration of about 50 mg / mL relative to the total volume of the composition.

[1068] In some embodiments, the composition comprising the non-naturally occurring melanocorticoid analogue is administered parenterally to the subject. In some embodiments, the composition comprising the non-naturally occurring melanocorticoid analogue is administered subcutaneously to the subject.

[1069] In some embodiments, compositions formulated for parenteral (e.g., subcutaneous) administration comprise a non-naturally occurring melanocortin analog of formula (I) at concentrations of about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol or higher (depending on the specific peptide selected, the desired reaction, the route of administration, the formulation, and other factors known to those skilled in the art). In some embodiments, the non-naturally occurring melanocortin analog comprises TCMCB07.

[1070] In some embodiments, non-natural melanocortin analogs cross the blood-brain barrier (BBB) ​​of the subject.

[1071] In some embodiments, the subject is a mammal, including but not limited to humans, non-human primates (such as chimpanzees), livestock or farm animals (such as cattle, bison, sheep, pigs, goats, horses, chickens, and roosters), domestic pets (such as dogs, cats, rats, mice, and rabbits), and laboratory subjects (such as rodents, including rats, mice, and guinea pigs). In some embodiments, the subject is a human. In some embodiments, the subject is an animal, such as a rat or a dog.

[1072] In some embodiments, the subject's body mass index (BMI) is 18.5 kg / m².2 Up to 25kg / m 2 In some embodiments, the subject's BMI is less than 20 kg / m². 2 In some embodiments, the subject's BMI is less than 18.5 kg / m². 2 .

[1073] In some embodiments, the subjects are underweight subjects. Underweight subjects include those whose weight is below the lower limit of the "normal" BMI (e.g., 18.5 kg / m²). 2 The percentage of subjects with a rate of approximately 3%, 5%, or lower, 10%, 20%, or 30% or lower is lower.

[1074] Compositions comprising the carrier and / or excipients of the present invention facilitate the delivery (e.g., parenteral administration, particularly subcutaneous injection) of non-natural melanocorticoid analogs to subjects. Other objectives of compositions comprising the carrier and / or excipients are to enhance the dispersibility, solubility, and stability of non-natural melanocorticoid analogs and to reduce adverse injection site reactions.

[1075] The carrier and / or excipients of the composition may typically include one or more of the following components: a pH-buffered aqueous solution comprising (a) sodium acetate, (b) Tris and (c) water. In some embodiments, all components are compatible with non-naturally occurring melanocortin analogs (i.e., do not react with or cause non-naturally occurring melanocortin analogs to react) and are uniformly dispersed or uniformly dissolved in the composition.

[1076] In some embodiments, the carrier and / or excipient are isotonic.

[1077] To achieve the desired tension, the compositions of the present invention may further comprise salts such as sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride. In some embodiments, the salts are present in the composition at concentrations of 0.1 mg / mL to 50 mg / mL, 1 mg / mL to 25 mg / mL, or 5 mg / mL to 10 mg / mL relative to the total volume of the composition.

[1078] The carrier and / or excipient of the composition further include a pH buffered aqueous solution comprising (a) sodium acetate, (b) Tris and (c) water.

[1079] The water used in this document may be used as a diluent, and includes, but is not limited to, water for injection (WFI), sterile water, bacteriostatic water for injection (BWFI), distilled water, double-distilled water, deionized water, deionized distilled water, and reverse osmosis water. In some embodiments, the water present in the pH buffer solution is water for injection.

[1080] In some embodiments, the composition comprises water in amounts of about 1 wt% to about 90 wt%, about 10 wt% to about 75 wt%, or about 25 wt% to about 50 wt% relative to the total weight of the composition.

[1081] In some embodiments, sodium acetate is present in the composition at a concentration of 0.5 mg / mL to 50 mg / mL relative to the total volume of the composition. For example, sodium acetate is present in the composition at concentrations of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL relative to the total volume of the composition.

[1082] In some embodiments, sodium acetate is present in the composition at a concentration of about 6 mg / mL to about 8 mg / mL relative to the total volume of the composition. For example, sodium acetate is present in the composition at a concentration of 6 mg / mL, 6.5 mg / mL, 7 mg / mL, 7.1 mg / mL, 7.5 mg / mL, or 8 mg / mL relative to the total volume of the composition.

[1083] In some embodiments, sodium acetate is present in the composition at a molar concentration of 5 mM to 700 mM relative to the total volume of the composition. Sodium acetate is present in the composition at molar concentrations of 5 mM to 700 mM, 10 mM to 600 mM, 20 mM to 500 mM, 30 mM to 400 mM, 40 mM to 300 mM, 50 mM to 200 mM, 60 mM to 100 mM, or 70 mM to 80 mM relative to the total volume of the composition.

[1084] In some embodiments, sodium acetate is present in the composition at a molar concentration of about 80 mM to about 100 mM relative to the total volume of the composition. For example, sodium acetate is present in the composition at a molar concentration of 80 mM, 85 mM, 87 mM, 90 mM, 95 mM or 100 mM relative to the total volume of the composition.

[1085] The term "Tris" refers to tris(hydroxymethyl)aminomethane, also known as Tris buffer, Tris base, TRIS, tromethamine, tromethamine buffer, etc. Trisamine, Trometamol, Tromethane, Trisaminol, or THAM. In some embodiments, Tris is present in the composition at a concentration of 0.5 mg / mL to 50 mg / mL relative to the total volume of the composition. For example, Tris is present in the composition at concentrations of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL relative to the total volume of the composition.

[1086] In some embodiments, Tris is present in the composition at a concentration of about 6 mg / mL to about 8 mg / mL relative to the total volume of the composition. For example, Tris is present in the composition at a concentration of 6 mg / mL, 6.5 mg / mL, 7 mg / mL, 7.3 mg / mL, 7.6 mg / mL or 8 mg / mL relative to the total volume of the composition.

[1087] In some embodiments, Tris is present in the composition at a molar concentration of 2 mM to 500 mM relative to the total volume of the composition. For example, Tris is present in the composition at a molar concentration of 2 mM to 500 mM, 5 mM to 400 mM, 10 mM to 300 mM, 20 mM to 200 mM, 30 mM to 150 mM, 40 mM to 100 mM, 50 mM to 80 mM, or 60 mM to 70 mM relative to the total volume of the composition.

[1088] In some embodiments, Tris is present in the composition at a molar concentration of about 50 mM to about 70 mM relative to the total volume of the composition. For example, Tris is present in the composition at a molar concentration of 50 mM, 55 mM, 60 mM, 65 mM or 70 mM relative to the total volume of the composition.

[1089] In some embodiments, the pH-buffered aqueous solution brings the pH of the composition to or near physiological pH levels. This can reduce adverse reactions at the injection site and give non-natural melanocortin analogs enhanced stability and resistance to aggregation and degradation.

[1090] In addition to sodium acetate and Tris, the composition may also contain other buffers. Non-limiting examples of other buffers include saline, phosphate, phosphoric acid, citrate, succinate, gluconate, histidine, acetic acid, ascorbate, tartaric acid, maleic acid, glycine, lactate, lactic acid, ascorbic acid, imidazole, bicarbonate, carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, ethylenediaminetetraacetic acid, malate, imidazole, and mixtures thereof. In some embodiments, the composition contains acetic acid as an additional buffer.

[1091] In some embodiments, the weight ratio of sodium acetate to Tris is 1:4 to 4:1, 2:7 to 7:2, 1:3 to 3:1, 2:5 to 5:2, 1:2 to 2:1, 2:3 to 3:2, or about 1:1. In some embodiments, the weight ratio of sodium acetate to Tris is about 1:1.

[1092] In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is 1:1 to 20:1, 3:2 to 15:1, 2:1 to 12:1, 3:1 to 10:1, 4:1 to 9:1, 5:1 to 8:1, or 6:1 to 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is about 7:1.

[1093] In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is 1:1 to 20:1, 3:2 to 15:1, 2:1 to 12:1, 3:1 to 10:1, 4:1 to 9:1, 5:1 to 8:1, or 6:1 to 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is about 7:1.

[1094] The composition may also contain preservatives. Exemplary preservatives include, but are not limited to, ascorbic acid, cysteine ​​hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, phenol, m-cresol, benzyl alcohol, α-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, benzalkonium chloride, phenoxyethanol, and methylparaben.

[1095] If present, the concentration of the preservative relative to the total volume of the composition can range from 0.001 mg / mL to 50 mg / mL, 0.01 mg / mL to 25 mg / mL, 0.1 mg / mL to 10 mg / mL, or 1 mg / mL to 5 mg / mL.

[1096] In some embodiments, the composition is in the form of an aqueous solution or a suspension. In some embodiments, the composition is in the form of an emulsion. In some embodiments, the composition is in the form of an aqueous solution. In some embodiments, the composition is in the form of an aqueous solution that is clear, colorless, and / or free of visible foreign matter.

[1097] In some embodiments, the pH range of the composition is 6.5 to 8.5. In some embodiments, the pH of the composition is about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5.

[1098] In some embodiments, the composition is alkaline and has a pH of about 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5. In some embodiments, the pH of the composition ranges from about 7.3 to about 7.4. In some embodiments, the pH of the composition is 7.3 or 7.4.

[1099] In some embodiments, the osmotic pressure of the composition ranges from 250 mOsm / kg to 350 mOsm / kg. For example, the osmotic pressure of the composition ranges from 250 mOsm / kg to 360 mOsm / kg, 260 mOsm / kg to 340 mOsm / kg, 270 mOsm / kg to 330 mOsm / kg, 280 mOsm / kg to 320 mOsm / kg, 290 mOsm / kg to 310 mOsm / kg, or about 300 mOsm / kg. In some embodiments, the osmotic pressure of the composition is about 250 mOsm / kg, about 260 mOsm / kg, about 270 mOsm / kg, about 280 mOsm / kg, about 290 mOsm / kg, about 300 mOsm / kg, about 310 mOsm / kg, about 320 mOsm / kg, about 330 mOsm / kg, about 340 mOsm / kg, about 350 mOsm / kg, or about 360 mOsm / kg. In some embodiments, the osmotic pressure of the composition ranges from about 275 mOsm / kg to about 330 mOsm / kg. In some embodiments, the osmotic pressure of the composition is about 279 mOsm / kg, about 314 mOsm / kg, or about 329 mOsm / kg.

[1100] In some embodiments, the viscosity of the composition ranges from 0.5 cP to 5 cP. For example, the viscosity range of the composition is 0.5 cP to 5 cP, 0.75 cP to 4.5 cP, 1.0 cP to 4 cP, 1.2 cP to 3.5 cP, 1.3 cP to 3 cP, 1.4 cP to 2.5 cP, 1.5 cP to 2 cP, or 1.6 cP to 1.8 cP. In some embodiments, the viscosity of the composition is about 0.5 cP, 0.6 cP, 0.7 cP, 0.8 cP, 0.9 cP, 1.0 cP, 1.1 cP, 1.2 cP, 1.3 cP, 1.4 cP, 1.5 cP, 1.6 cP, 1.7 cP, 1.8 cP, 1.9 cP, or 2.0 cP. In some embodiments, the viscosity of the composition is about 1.4 cP or 1.6 cP.

[1101] The compositions of this invention can be formulated for parenteral administration, for example, in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. As used herein, the term "parenteral" includes subcutaneous, intravenous, intraperitoneal, intramuscular, and intralesional administration or infusion techniques.

[1102] One or more active ingredients (e.g., non-natural melanocortin analogs) may be dissolved or suspended in the aforementioned carriers and / or excipients. Additional aqueous or non-aqueous carriers that may promote the dissolution of the active ingredient include, but are not limited to, ethanol, benzyl alcohol, DMSO, polyethylene glycol, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, and / or various buffer solutions.

[1103] In some embodiments, compositions formulated for parenteral (e.g., subcutaneous) administration comprise a non-natural melanocortin analogue at concentrations of about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol or higher (depending on the specific peptide selected, the desired therapeutic response, the route of administration, the formulation, and other factors known to those skilled in the art).

[1104] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises concentrations of about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 76 mM, 77 mM, 78 mM, 79 mM, 80 mM, 81 mM, 82 mM, 83 mM, 84 mM, etc. Sodium acetate in the following concentrations: mM, 85mM, 86mM, 87mM, 88mM, 89mM, 90mM, 91mM, 92mM, 93mM, 94mM, 95mM, 96mM, 97mM, 98mM, 99mM, 100mM, 105mM, 110mM, 120mM, 130mM, 140mM, 150mM, 160mM, 170mM, 180mM, 190mM, or 200mM.

[1105] In some embodiments, the composition formulated for parenteral (e.g., subcutaneous) administration comprises Tris at concentrations of about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, or 120 mM.

[1106] The compositions of this invention can be formulated for intranasal delivery. In some embodiments, the intranasal composition comprises a non-naturally occurring melanocortin analog of this invention, as well as a carrier and / or excipients.

[1107] The carrier and / or excipients of the composition may typically comprise one or more of the following components: (i) one or more antioxidants, (ii) one or more preservatives, (iii) one or more buffers, (iv) one or more tension modifiers, (v) one or more surfactants, (vi) fragrances, (vii) propellants, and / or (viii) mediators or solvents. In some embodiments, all components are compatible with non-naturally occurring melanocortin analogs (i.e., do not react with or cause reactions with non-naturally occurring melanocortin analogs) and are uniformly dispersed or uniformly dissolved in the composition.

[1108] In some embodiments, the carrier and / or excipient are isotonic with nasal fluid.

[1109] To achieve the desired tension, the compositions of the present invention may further comprise salts such as sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride. In some embodiments, the salt is present in the composition at a concentration of 0.1 mg / mL to 50 mg / mL, 1 mg / mL to 25 mg / mL, or 5 mg / mL to 10 mg / mL relative to the total volume of the composition. In some aspects, the salt is sodium chloride at a concentration of 0.9% wt.

[1110] The carrier and / or excipient of the composition also include a pH-buffered aqueous solution, which includes a pH-buffered aqueous solution of sodium acetate, Tris and water.

[1111] The water used in this document may be used as a diluent, and includes, but is not limited to, water for injection (WFI), sterile water, bacteriostatic water for injection (BWFI), distilled water, double-distilled water, deionized water, deionized distilled water, and reverse osmosis water. In some embodiments, the water present in the pH buffer solution is water for injection.

[1112] In some embodiments, the composition comprises water (e.g., water for injection) in amounts of about 1 wt% to about 90 wt%, about 10 wt% to about 75 wt%, or about 25 wt% to about 50 wt% relative to the total weight of the composition.

[1113] In some embodiments, sodium acetate is present in the composition at a concentration of 0.5 mg / mL to 50 mg / mL relative to the total volume of the composition. For example, sodium acetate is present in the composition at concentrations of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL relative to the total volume of the composition.

[1114] In some embodiments, sodium acetate is present in the composition at a molar concentration of about 80 mM to about 100 mM relative to the total volume of the composition. For example, sodium acetate is present in the composition at a molar concentration of 80 mM, 85 mM, 87 mM, 90 mM, 95 mM or 100 mM relative to the total volume of the composition.

[1115] The term "Tris" refers to tris(hydroxymethyl)aminomethane, also known as Tris buffer, Tris base, TRIS, tromethamine, tromethamine buffer, etc. Trisamine, Trometamol, Tromethane, Trisaminol, or THAM. In some embodiments, Tris is present in the composition at a concentration of 0.5 mg / mL to 50 mg / mL relative to the total volume of the composition. For example, Tris is present in the composition at concentrations of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL relative to the total volume of the composition.

[1116] In some embodiments, the pH-buffered aqueous solution brings the pH of the composition to or near physiological pH levels. This can reduce adverse reactions at the injection site and give non-natural melanocortin analogs enhanced stability and resistance to aggregation and degradation.

[1117] In addition to sodium acetate and Tris, the composition may also contain other buffers. Non-limiting examples of other buffers include saline, phosphate, phosphoric acid, citrate, succinate, gluconate, histidine, acetic acid, ascorbate, tartaric acid, maleic acid, glycine, lactate, lactic acid, ascorbic acid, imidazole, bicarbonate, carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, ethylenediaminetetraacetic acid, malate, imidazole, and mixtures thereof. In some embodiments, the composition contains acetic acid as an additional buffer.

[1118] In some embodiments, sodium phosphate is present in the composition at a molar concentration of 5 mM to 700 mM relative to the total volume of the composition. Sodium acetate is present in the composition at a molar concentration of 5 mM to 700 mM, 10 mM to 600 mM, 20 mM to 500 mM, 30 mM to 400 mM, 40 mM to 300 mM, 50 mM to 200 mM, 60 mM to 100 mM, or 70 mM to 80 mM relative to the total volume of the composition.

[1119] The composition may also contain preservatives. Exemplary preservatives include, but are not limited to, ascorbic acid, cysteine ​​hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, phenol, m-cresol, benzyl alcohol, benzalkonium chloride, α-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, benzalkonium chloride, phenoxyethanol, and methylparaben.

[1120] If present, the concentration of the preservative relative to the total volume of the composition can range from 0.001 mg / mL to 50 mg / mL, 0.01 mg / mL to 25 mg / mL, 0.1 mg / mL to 10 mg / mL, or 1 mg / mL to 5 mg / mL.

[1121] In some embodiments, the composition is in the form of an aqueous solution or a suspension. In some embodiments, the composition is in the form of an emulsion. In some embodiments, the composition is in the form of an aqueous solution. In some embodiments, the composition is in the form of an aqueous solution that is clear, colorless, and / or free of visible foreign matter.

[1122] In some embodiments, the pH of the composition is close to the normal pH range of nasal fluids. In some embodiments, the pH range of the composition is 5.5 to 6.5. In some embodiments, the pH of the composition is about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, or 6.5.

[1123] In some embodiments, the osmotic pressure of the composition ranges from 250 mOsm / kg to 350 mOsm / kg. For example, the osmotic pressure of the composition ranges from 250 mOsm / kg to 360 mOsm / kg, 260 mOsm / kg to 340 mOsm / kg, 270 mOsm / kg to 330 mOsm / kg, 280 mOsm / kg to 320 mOsm / kg, 290 mOsm / kg to 310 mOsm / kg, or about 300 mOsm / kg. In some embodiments, the osmotic pressure of the composition is about 250 mOsm / kg, about 260 mOsm / kg, about 270 mOsm / kg, about 280 mOsm / kg, about 290 mOsm / kg, about 300 mOsm / kg, about 310 mOsm / kg, about 320 mOsm / kg, about 330 mOsm / kg, about 340 mOsm / kg, about 350 mOsm / kg, or about 360 mOsm / kg. In some embodiments, the osmotic pressure of the composition ranges from about 275 mOsm / kg to about 330 mOsm / kg. In some embodiments, the osmotic pressure of the composition is about 279 mOsm / kg, about 314 mOsm / kg, or about 329 mOsm / kg.

[1124] In some embodiments, the viscosity of the composition ranges from 0.5 cP to 5 cP. For example, the viscosity range of the composition is 0.5 cP to 5 cP, 0.75 cP to 4.5 cP, 1.0 cP to 4 cP, 1.2 cP to 3.5 cP, 1.3 cP to 3 cP, 1.4 cP to 2.5 cP, 1.5 cP to 2 cP, or 1.6 cP to 1.8 cP. In some embodiments, the viscosity of the composition is about 0.5 cP, 0.6 cP, 0.7 cP, 0.8 cP, 0.9 cP, 1.0 cP, 1.1 cP, 1.2 cP, 1.3 cP, 1.4 cP, 1.5 cP, 1.6 cP, 1.7 cP, 1.8 cP, 1.9 cP, or 2.0 cP. In some embodiments, the viscosity of the composition is about 1.4 cP or 1.6 cP.

[1125] In some embodiments, the composition comprises one or more antioxidants. For example, the composition may comprise ascorbic acid, cysteine, sodium metabisulfite, propyl gallate, butylated hydroxytoluene, and / or butylated hydroxyanisole.

[1126] In some embodiments, the composition comprises a surfactant, such as sorbitol ester.

[1127] In some embodiments, the composition comprises a flavoring agent or fragrance, such as an aromatic oil.

[1128] One or more active ingredients (e.g., non-natural melanocortin analogs) may be dissolved or suspended in the aforementioned carriers and / or excipients. Additional aqueous or non-aqueous carriers that may promote the dissolution of the active ingredient include, but are not limited to, ethanol, benzyl alcohol, DMSO, polyethylene glycol, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, and / or various buffer solutions.

[1129] In some embodiments, a non-naturally occurring melanocortin analogue is dissolved or suspended in a solvent or medium. In some embodiments, the solvent or medium is purified water, ethanol, or propylene glycol. The composition may contain between 0.03% wt and 1% wt of melanocortin dissolved or suspended in a solvent or medium. The composition may contain about 0.03% wt, 0.05% wt, 0.1% wt, 0.15% wt, 0.2% wt, 0.25% wt, 0.3% wt, 0.35% wt, 0.4% wt, 0.45% wt, 0.5% wt, 0.55% wt, 0.6% wt, 0.65% wt, 0.7% wt, 0.75% wt, 0.8% wt, 0.85% wt, 0.9% wt, 0.95% wt, or 1% wt of a non-naturally occurring melanocortin analogue.

[1130] In some embodiments, the composition formulated for intranasal application comprises a non-naturally occurring melanocortin analogue at concentrations of about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol or higher (depending on the specific peptide selected, the desired therapeutic response, the route of administration, the formulation, and other factors known to those skilled in the art).

[1131] The composition can be formulated for delivery via nasal drops, a spray device, or a topical solution. In some embodiments, the pharmaceutical composition can be formulated as an aerosol, nebulizer, inhaler, blow-in, metered-dose inhaler, or nebulizer. In some embodiments, the composition comprises a propellant, such as hydrofluorocarbon.

[1132] In some embodiments, the composition may be configured to be administered using a spray device or a nasal inhaler. The spray device or nasal inhaler may be configured to deliver 1 μg to 100 μg per spray. In some embodiments, the spray device or nasal inhaler may be configured to deliver 1 μg to 100 μg, 5 μg to 90 μg, 10 μg to 80 μg, 15 μg to 70 μg, 20 μg to 60 μg, 25 μg to 50 μg, or 30 μg to 40 μg per spray.

[1133] Further examples of non-natural melanocortin analogues

[1134] Further aspects of non-naturally occurring melanocortin analogues that can be used in the methods of the present invention are described below.

[1135] Cyclated melanocortin analogues have shown improved efficacy and stability. See Balse-Srinivasan et al., J. Med. Chem. 46(17):3728-3733 (2003) and Bednarek et al., Biochem. Biophys. Res. Com. 286(3):641-645 (2001); Kavarana et al., J. Med. Chem. 45(12):2644-2650 (2002). In one respect, non-naturally occurring melanocortin analogues represented by Formula (I) are cyclized. The following is a list of non-limiting examples of how non-naturally occurring melanocortin analogues represented by Formula (I) can be cyclized:

[1136] In equation I, when R 1 Or R 2 For cysteine ​​and R7 Or Y 1 When it is cysteine, R 1 Or R 2 With R 7 Or Y 1 The disulfide bond between them, as described in Balse-Srinivasan et al., J. Med. Chem., 2003, 46(23):4965-4973. When Y 1 When cysteine ​​is present, Y 2 It does not not exist, but it is selected from the group consisting of the following: D-threonine, L-threonine, D-proline, L-proline, and piperazine-2-one ring.

[1137] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 Lactam bridges between them, such as Mayorov et al. J.Med.Chem.49:1946-1952 (2006) and Bednarek et al., Biochem.Biophys.Res.Com.286(3):641-645 (2001).

[1138] When R 2 It is glutamic acid or aspartic acid and R 7 When it is lysine, R 2 With R 7 The side-chain lactam bridges between them, such as Bednarek et al., Biochem. Biophys. Res. Com. 286(3):641-645 (2001).

[1139] When R 1 It is succinic acid or phthalic acid and R 7 When it is lysine, R 1 With R 7 Lactam bridges between them, such as Bednarek et al., Biochem. Biophys. Res. Com. 286(3):641-645 (2001) and Kavarana et al., J. Med. Chem. 45(12):2644-2650 (2002).

[1140] When R 2 Or R 3 It is succinic acid and R 7 When it is 2,3-diamino-propionic acid, R 2 Or R 3 With R 7Lactam bridges between them, such as Bednarek et al., Biochem. Biophys. Res. Com. 286(3):641-645 (2001).

[1141] “Skeleton” cyclic peptides are formed by covalent bonding between the C-terminus and / or N-terminus of the target linear peptide. This example is described as two amide nitrogens connected by a bridge bond consisting of an alkyl group and an amide, as described in Hess et al., J. Med. Chem. 50:6201-6211 (2007).

[1142] peptide synthesis

[1143] The non-naturally occurring melanocortin analogues of the present invention can be readily synthesized using any known conventional procedure for forming peptide bonds between amino acids. Such conventional procedures include, for example, any solution-phase procedure that allows condensation between a free α-amino group of an amino acid or residue having a protected carboxyl group or other reactive group and a free primary carboxyl group of another amino acid or residue having a protected amino group or other reactive group. In an exemplary procedure, the peptides of the present invention can be synthesized by solid-phase synthesis and purified according to methods known in the art. Any well-known method can be used to prepare the peptides of the present invention using various resins and reagents.

[1144] Peptide synthesis can be performed by sequentially adding each amino acid in the desired sequence to another amino acid or residue thereof; or by first conventionally synthesizing a peptide fragment having the desired amino acid sequence, then condensing it to provide the desired peptide. The resulting peptide is then cyclized to produce a cyclic peptide.

[1145] Solid-phase peptide synthesis methods are well-known and practiced in the art. In such methods, peptide synthesis is carried out by sequentially incorporating desired amino acid residues one by one into a growing peptide chain, according to the general principles of solid-phase methods. These methods are disclosed in numerous references, including Merrifield, Angew Chem. 24:799-810 (1985) and Barany et al., The Peptides, Analysis, Synthesis and Biology, Vol. 2, Gross E. and Meienhofer J., eds., Academic Press 1-284 (1980).

[1146] In the chemical synthesis of peptides, reactive side chain groups of various amino acid residues are protected with appropriate protecting groups to prevent chemical reactions at that site until the protecting groups are removed. Another common approach is to protect the α-amino group of the entity when the amino acid residue or fragment reacts at the carboxyl group, and then selectively remove the α-amino protecting group to allow subsequent reactions to occur at that site. Specific protecting groups used in solid-phase and solution-phase synthesis methods are known to those skilled in the art.

[1147] The α-amino group can be protected by suitable protecting groups, including urethane protecting groups such as benzyloxycarbonyl (Z); and substituted benzyloxycarbonyl groups such as p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-biphenyl-isopropoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc), and p-methoxybenzyloxycarbonyl (Moz); aliphatic urethane protecting groups such as tert-butoxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc can be used for α-amino group protection.

[1148] The guanidino group can be protected by a suitable protecting group, such as nitro, p-toluenesulfonyl (Tos), Z, pentamethylsaturonyl (Pmc), adamantyloxycarbonyl, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), and Boc. Pmc is a useful protecting group for Arg.

[1149] Solid-phase synthesis begins at the C-terminus of the peptide by coupling the protected α-amino acid to a suitable resin. Such starting materials are prepared by attaching the α-amino-protected amino acid to a p-benzyloxybenzyl alcohol (Wang) resin or a 2-chlorotriphenylmethyl chloride resin via an ester bond, or via an Fmoc-linker, such as an amide bond between p-((R,S)-α-(1-(9H-fluoro-en-9-yl)-methoxyformamido)-2,4-dimethyloxybenzyl)-phenoxyacetic acid (Rink linker) and a diphenylmethylamine (BHA) resin, or by other methods known in the art. Fmoc-linker-BHA resin supports are commercially available and are typically used where feasible. The resin is repeatedly cycled as needed to sequentially add amino acids. The α-amino Fmoc protecting group is removed under alkaline conditions. For this purpose, piperidine, piperazine, diethylamine, or morpholine (20% to 40% v / v) in N,N-dimethylformamide (DMF) can be used.

[1150] After removing the α-amino protecting group, the subsequent protected amino acids are sequentially coupled to obtain the intermediate, i.e., the protected peptide resin. Activating agents used for amino acid coupling in solid-phase peptide synthesis are well known in the art. Following peptide synthesis, if desired, orthogonally protected side-chain protecting groups can be removed using methods well known in the art for further peptide derivatization.

[1151] The reactive groups in a peptide can be selectively modified during solid-phase synthesis or after removal from the resin. For example, a peptide can be modified on the resin to obtain an N-terminal modification, such as acetylation, or it can be modified after removal from the resin using a cleavage reagent. Methods for N-terminal modifications (such as acetylation) and C-terminal modifications (such as amidation) are known in the art. Similarly, methods for modifying amino acid side chains are well known to those skilled in the art of peptide synthesis. The choice of modification for the reactive groups present on the peptide will depend in part on the desired characteristics of the peptide.

[1152] Peptides can be cyclized before cleavage from a peptide resin. For cyclization via reactive side chains, the desired side chain is deprotected, the peptide is suspended in a suitable solvent, and a cyclic coupling agent is added. Suitable solvents include, for example, DMF, dichloromethane (DCM), or 1-methyl-2-pyrrolidone (NMP). Suitable cyclic coupling agents include, for example, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium tetrafluoroborate (TBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate (HBTU), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris(pyrrolidone)-phosphonium hexafluorophosphate, etc. The coupling is initiated using pyrophosphonium hexafluorophosphate (PyBOP), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon tetrafluoroborate (TATU), 2-(2-oxo-1(2H)-pyridyl)-1,1,3,3-tetramethylureon tetrafluoroborate (TPTU), or N,N'-dicyclohexylcarbodiimide / 1-hydroxybenzotriazole (DCCl / HOBt). Coupling is initially initiated using a suitable base (such as N,N-diisopropylethylamine (DIPEA), symmetrical chloromethol, or N-methylmorpholine (NMM)).

[1153] After peptide synthesis, the peptide can be cleaved from the solid phase using various methods (such as using a suitable column, such as C). 18 The peptide is purified by reversed-phase high-performance liquid chromatography (RP-HPLC) using a column. Other separation or purification methods, such as those based on peptide size or charge, can also be used. Once purified, the peptide can be characterized using various methods, such as HPLC, amino acid analysis, and mass spectrometry.

[1154] Salt form of peptide

[1155] The non-naturally occurring melanocortin analog peptides of this invention can be in the form of any salt. The term "pharmaceutically acceptable salt" refers to a salt prepared from a non-toxic base or acid (including inorganic or organic bases and inorganic or organic acids). Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese dioxide salts, potassium salts, sodium salts, zinc salts, etc. Exemplary salts include ammonium salts, calcium salts, lithium salts, magnesium salts, potassium salts, and sodium salts. Salts derived from organic non-toxic alkalis include salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and salts of basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, heparin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[1156] When the peptide of this invention is basic, acid addition salts can be prepared from non-toxic acids (including inorganic and organic acids). Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carboxylic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, malonic acid, viscous acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid, etc. The acid addition salts of the peptides of this invention are prepared in a suitable solvent from the peptide and an excess of acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, citric acid, tartaric acid, maleic acid, succinic acid, or methanesulfonic acid). The acetate form is particularly suitable. When the peptide of the present invention contains an acidic portion, a suitable salt may include an alkali metal salt (such as a sodium or potassium salt) or an alkaline earth metal salt (such as a calcium or magnesium salt).

[1157] Pharmacokinetics and Pharmacodynamics

[1158] The non-natural melanocortin analogues of the present invention exhibit pharmacokinetic (pK) and / or pharmacodynamic (pD) parameters. Such pK and / or pD may be expressed relative to a control or otherwise determined, which in some cases may be a non-natural melanocortin analogue lacking one or more characteristics of the non-natural melanocortin analogue of the present invention.

[1159] In some embodiments, the pK and / or pD of non-naturally occurring melanocortin analogues can be measured using concentration and / or time (e.g., T).最终 C max T1 / 2(h)), AUC or T max An evaluation was conducted. In some embodiments, non-naturally occurring melanocortin analogs, compared to a control, exhibited reduced clearance and / or metabolism, increased uptake, absorption, and / or stability.

[1160] Clear

[1161] "Clearance" can refer to the elimination, absorption, and / or metabolism of non-naturally occurring melanocortin analogues in a subject's plasma. Clearance can be assessed as the plasma volume of non-naturally occurring melanocortin analogues cleared over time (e.g., mL / min, L / hr, or L / day), and / or can be normalized relative to the subject's body weight (e.g., mL / min / kg). Decreased clearance can also be assessed by an increased half-life or volume of distribution (V). d This is represented by ) . In some embodiments, measuring clearance includes measuring the terminal clearance rate constant (λ) z (Q) or inter-room clearance.

[1162] In some embodiments, the reduction in clearance includes measurements taken approximately 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week after application of a non-naturally occurring melanocorticoid analogue.

[1163] In some embodiments, the reduction in clearance includes measurements taken during the application of a non-naturally occurring melanocortin analogue. In some embodiments, the reduction in clearance includes measurements taken upon completion of the application of the non-naturally occurring melanocortin analogue.

[1164] concentration

[1165] In some embodiments, the non-naturally occurring melanocortin analogues of the present invention comprise increased tissue, plasma, and / or serum concentrations relative to a control. "Concentration" may include measurements reflecting one or more of the absolute amount of the non-naturally occurring melanocortin analogue, its absorption, metabolism, or elimination.

[1166] Increased tissue, plasma, and / or serum concentrations can be an increase in the concentration of a non-naturally occurring melanocortin analogue at a given time point relative to a control administered at the same dose and measured at the same time point. Concentrations can be measured at intermediate or final time points and can be measured as mean residence time (MRT), mean concentration (C), etc. avg ), trough concentration (C) 谷) or the concentration at the end of administration (e.g., infusion) (C T ).

[1167] In some embodiments, the increased concentration is achieved through peak plasma concentration (C). max The increase in ) reflects this. C max An increase in [amount] can indicate increased absorption, decreased metabolism, or slowed elimination of non-natural melanocortin analogs relative to a control. In some embodiments, C max C including dose normalization max (DNC max ).

[1168] In some embodiments, the increased concentration is achieved through a minimum plasma concentration (C0). min The increase in ) reflects this. C min An increase in [amount] can indicate increased absorption, decreased metabolism, or slowed elimination of non-natural melanocortin analogs relative to a control. In some embodiments, C min C including dose normalization min (DNC min ).

[1169] In some embodiments, the increased concentration is achieved by reaching C max Time (T) max The decrease in T reflects this. max This can indicate, compared to a control, increased absorption, decreased metabolism, or slowed elimination of non-natural melanocortin analogs.

[1170] In some embodiments, the increased concentration is achieved through a final measurable concentration (T). 最终 This reflects the increase in T. 最终 This can indicate, compared to a control, increased absorption, decreased metabolism, or slowed elimination of non-natural melanocortin analogs.

[1171] In some embodiments, the increased concentration is reflected by an increase in the area under the curve (AUC). An increase in AUC may indicate increased exposure to non-naturally occurring melanocortin analogues, and / or may indicate increased absorption, decreased metabolism, or slowed elimination of non-naturally occurring melanocortin analogues compared to a control group. AUC measurements may include the area under the curve (DNAUC) of drug concentrations in non-compartmental analyses.

[1172] In some embodiments, the increase in tissue, plasma, and / or serum concentrations includes measurements taken approximately 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week after administration of a non-naturally occurring melanocorticoid analogue.

[1173] In some embodiments, an increase in tissue, plasma, and / or serum concentrations includes measurements taken at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week after administration of a non-naturally occurring melanocorticoid analogue.

[1174] In some embodiments, an increase in tissue, plasma, and / or serum concentrations includes measurements taken at least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week after administration of a non-naturally occurring melanocorticoid analogue.

[1175] In some embodiments, increases in tissue, plasma, and / or serum concentrations include measurements taken during administration of a non-naturally occurring melanocorticoid analogue.

[1176] In some embodiments, the increase in tissue, plasma, and / or serum concentrations includes measurements taken upon completion of administration of a non-naturally occurring melanocorticoid analogue.

[1177] distributed

[1178] In some embodiments, the non-naturally occurring melanocortin analogues of the present invention comprise an increased distribution relative to a control. The increased distribution can be an increase in the distribution of the non-naturally occurring melanocortin analogue at a given time point relative to a control administered at the same dose and measured at the same time point. The distribution can be measured at intermediate or final time points.

[1179] In some embodiments, the measurement of distribution includes measuring the terminal distribution volume (Vt). d or V dβ Central distribution volume (V), peripheral distribution volume (V2), apparent distribution volume (V) z ), or the measurement of the distribution includes measuring the steady-state distribution volume (V ss High or increased V d V dβ V z and / or V ssThis can indicate a large distribution outside the tissue, plasma, and / or serum compartments compared to the control.

[1180] In some embodiments, the increase in distribution includes measurements taken approximately 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week after application of a non-naturally occurring melanocorticoid analogue.

[1181] In some embodiments, the increase in distribution includes measurements taken at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week after application of a non-naturally occurring melanocorticoid analogue.

[1182] In some embodiments, the increase in distribution includes measurements taken at least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week after application of a non-naturally occurring melanocorticoid analogue.

[1183] In some embodiments, the increase in distribution includes measurements taken during the application of a non-naturally occurring melanocortin analogue.

[1184] In some embodiments, the increase in distribution includes measurements taken upon completion of the application of a non-naturally occurring melanocortin analogue.

[1185] Other pD and pK embodiments

[1186] In some embodiments, the non-naturally occurring melanocortin analogues of the present invention exhibit one or more of the following:

[1187] (a) The half-life increased compared to the control;

[1188] (b) Clearance was reduced compared to the control;

[1189] (c) Tissue concentration increased compared to the control;

[1190] (d) Compared to the control, plasma concentration increased;

[1191] (e) Serum concentration increased compared to the control;

[1192] (f) The distribution increased compared to the control;

[1193] (g) The AUC measurement increased compared to the control;

[1194] (h) DNAUC measurements increased compared to the control;

[1195] (i) Compared to the control, T 最终 Increase;

[1196] (j) Compared to the control, C max Increase;

[1197] (k) Compared to the control, C min Increase;

[1198] (l) Compared to the control, DNC min Increase;

[1199] (m) Compared to the control, MRT increased;

[1200] (n) Compared to the control, C avg Increase;

[1201] (o) Compared to the control, C 谷 Increase;

[1202] (p) Compared to the control, C T Increase;

[1203] (q) Compared to the control, V d Increase;

[1204] (r) Compared to the control, T max Reduce; or

[1205] (s) Q decreased compared to the control.

[1206] In some embodiments, relative to the control, one or more of the following are non-natural melanocortin analogs of the present invention:

[1207] (a) The half-life is increased by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% compared to the control;

[1208] (b) Compared with the control, clearance was reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%;

[1209] (c) The tissue concentration increased by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% compared to the control;

[1210] (d) Compared with the control, plasma concentration increased by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%;

[1211] (e) The serum concentration increased by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% compared to the control;

[1212] (f) The distribution increased by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% compared to the control;

[1213] (g) The AUC increases by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% of the measured value compared to the control;

[1214] (h) The DNAUC measurement value increased by at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% compared to the control;

[1215] (i) Compared to the control, T 最终Increase by at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%.

[1216] (j) Compared to the control, C max Increase by at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%.

[1217] (k) Compared to the control, C min Increase by at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%.

[1218] (l) Compared to the control, DNC min Increase by at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%.

[1219] (m) Compared to the control, MRT increased by at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%;

[1220] (n) Compared to the control, C avg Increase by at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%.

[1221] (o) Compared to the control, C 谷Increase by at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%.

[1222] (p) Compared to the control, C T Increase by at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%.

[1223] (q) Compared to the control, V d Increase by at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%.

[1224] (r) Compared to the control, T max Reduce by at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%; or

[1225] (s) Q was reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to the control.

[1226] Related methods

[1227] This invention provides a method for stimulating appetite and / or increasing weight in subjects with kidney and / or liver disease. The method comprises administering a therapeutically effective amount of a non-naturally occurring melanocortin analogue to the subject. This method can promote appetite and food consumption, and increase or maintain the subject's weight, muscle mass, and / or fat mass. This method can also effectively treat anorexia, weight loss, muscle loss, fat loss, emaciation, decreased appetite, loss of appetite, nausea, vomiting, and symptoms associated with hypermetabolic immune-inflammatory syndrome in subjects of this invention (e.g., subjects with kidney and / or liver disease).

[1228] Subject characteristics

[1229] Kidney and liver diseases:

[1230] Subjects to this invention may have or be at risk of developing kidney and / or liver disease. Kidney and / or liver disease suitable for the methods of this invention can be any kidney and / or liver disease known to those skilled in the art. For example, kidney disease may include chronic kidney disease (CKD) and / or kidney failure (e.g., chronic renal failure). Liver disease may include non-alcoholic fatty liver disease (NAFLD), such as non-alcoholic steatohepatitis (NASH). Kidney and / or liver disease may be fibrotic. In some embodiments, kidney and / or liver disease may cause fatigue, weakness, nausea, anorexia, cachexia, loss of appetite, decreased food consumption, and / or weight loss.

[1231] In some embodiments, the subject has kidney disease. In some embodiments, kidney disease includes CKD and / or kidney failure.

[1232] In some embodiments, the subject has undergone or is undergoing dialysis. Non-limiting examples of dialysis include peritoneal dialysis and hemodialysis. In some embodiments, the subject has undergone or is undergoing a kidney transplant.

[1233] In some embodiments, in addition to, or in lieu of, the kidney disease of the present invention, the subject may have renal dysfunction and / or kidney damage.

[1234] In some embodiments, the subject has a liver disease. Non-limiting examples of liver disease include NAFLD, NASH, alcoholic liver disease, viral hepatitis, hemochromatosis, drug-induced hepatitis, Wilson's disease, sclerosing cholangitis, primary biliary cirrhosis, Budd-Kiali syndrome, venous occlusive disease, autoimmune hepatitis, steatohepatitis, partial hepatectomy, or Reye's syndrome. In some embodiments, the liver disease is NAFLD. In some embodiments, NAFLD is NASH.

[1235] BMI, weight, appetite, and related characteristics:

[1236] In some embodiments, the subject's body mass index (BMI) is 18.5 kg / m². 2 Up to 35kg / m 2 In some embodiments, the subject's BMI is less than 20 kg / m². 2 In some embodiments, the subject's BMI is less than 18.5 kg / m². 2 .

[1237] In some embodiments, the subjects are underweight subjects. Underweight subjects include those whose weight is below the lower limit of the "normal" BMI (e.g., 18.5 kg / m²).2 The percentage of subjects with a rate of approximately 3%, 5%, or lower, 10%, 20%, or 30% or lower is lower.

[1238] In some embodiments, the subjects are patients who have experienced involuntary weight loss before starting administration. For example, subjects are patients who have experienced a weight loss of 1%, 2%, 5%, or 10% per month for at least 2 months, at least 3 months, at least 6 months, at least 9 months, or at least 12 months per month before starting administration.

[1239] In some embodiments, subjects experienced loss of appetite, decreased appetite, reduced food consumption, and / or weight loss before administration.

[1240] In some embodiments, the loss of appetite, decreased appetite, reduced food consumption, and / or weight loss are caused by the kidney disease and / or the liver disease.

[1241] In some embodiments, the loss of appetite, decreased appetite, reduced food consumption, and / or weight loss are caused by cachexia.

[1242] In some embodiments, a subject is considered cachectic if they meet the Fearon weight loss criteria. Whether a subject meets the Fearon criteria can be determined using methods known to those skilled in the art. In some embodiments, the Fearon weight loss criteria include (1) a weight loss of more than 5% in the preceding 6 months or (2) a weight loss of more than 2%, wherein the subject's BMI is less than 20 kg / m². 2 The subject may have sarcopenia. Whether a subject has sarcopenia can be determined using methods known to those skilled in the art.

[1243] Other characteristics of the subjects:

[1244] In some embodiments, the subject is a mammal, including but not limited to humans, non-human primates (such as chimpanzees), livestock or farm animals (such as cattle, bison, sheep, pigs, goats, horses, chickens, and roosters), domestic pets (such as dogs, cats, rats, mice, and rabbits), and laboratory subjects (such as rodents, including rats, mice, and guinea pigs). In some embodiments, the subject is a human. In some embodiments, the subject is an animal, such as a rat or a dog.

[1245] Dosage

[1246] Typically, the actual amount of pharmaceutical composition administered to a subject can vary widely depending on the administration method, the formulation used, and the desired response. The therapeutic dose is administered by any of the methods described above or any other method known in the art, and is sufficient to produce the desired therapeutic effect. Therefore, a therapeutically effective amount includes an amount of peptides (e.g., non-naturally occurring melanocortin analogs of the present invention) or pharmaceutical compositions sufficient to increase weight and / or food consumption in metabolically unchallenged subjects. In some embodiments, a therapeutically effective amount includes an amount of peptides (e.g., non-naturally occurring melanocortin analogs of the present invention) that alleviates a patient's eating disorder; or an amount that prevents or delays the onset or recurrence of an eating disorder; or an amount used to manage a patient with a disease or symptom associated with cachexia (including those secondary to immune disorders and impairments) or other diseases and conditions of the present invention.

[1247] In some embodiments, in terms of mg of non-naturally occurring melanocortin analogue / subject weight (kg), the therapeutically effective amount of non-naturally occurring melanocortin analogue (e.g., for stimulating the subject's appetite) ranges from about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 90 mg / kg, about 0.1 mg / kg to about 80 mg / kg, about 0.5 mg / kg to about 70 mg / kg, about 1 mg / kg to about 60 mg / kg, about 1.2 mg / kg to about 50 mg / kg, about 1.4 mg / kg to about 40 mg / kg, about 1.6 mg / kg to about 30 mg / kg, about 1.8 mg / kg to about 20 mg / kg, about 2 mg / kg to about 10 mg / kg, about 2.2 mg / kg to about 5 mg / kg, about 2.4 mg / kg to about 3 mg / kg, or about 2.5 mg / kg.

[1248] In some embodiments, the therapeutically effective amount of a non-naturally occurring melanocortin analogue ranges from at least 0.001 mg / kg to at least 100 mg / kg, at least 0.01 mg / kg to at least 90 mg / kg, at least 0.1 mg / kg to at least 80 mg / kg, at least 0.5 mg / kg to at least 70 mg / kg, at least 1 mg / kg to at least 60 mg / kg, at least 1.2 mg / kg to at least 50 mg / kg, at least 1.4 mg / kg to at least 40 mg / kg, at least 1.6 mg / kg to at least 30 mg / kg, at least 1.8 mg / kg to at least 20 mg / kg, at least 2 mg / kg to at least 10 mg / kg, at least 2.2 mg / kg to at least 5 mg / kg, at least 2.4 mg / kg to at least 3 mg / kg, or at least 2.5 mg / kg.

[1249] In some embodiments, the therapeutically effective amount of a non-naturally occurring melanocortin analogue ranges from at least about 0.001 mg / kg to at least about 100 mg / kg, at least about 0.01 mg / kg to at least about 90 mg / kg, at least about 0.1 mg / kg to at least about 80 mg / kg, at least about 0.5 mg / kg to at least about 70 mg / kg, at least about 1 mg / kg to at least about 60 mg / kg, at least about 1.2 mg / kg to at least about 50 mg / kg, at least about 1.4 mg / kg to at least about 40 mg / kg, at least about 1.6 mg / kg to at least about 30 mg / kg, at least about 1.8 mg / kg to at least about 20 mg / kg, at least about 2 mg / kg to at least about 10 mg / kg, at least about 2.2 mg / kg to at least about 5 mg / kg, at least about 2.4 mg / kg to at least about 3 mg / kg, or at least about 2.5 mg / kg.

[1250] In some embodiments, the therapeutically effective dose of a non-naturally occurring melanocortin analogue, based on the subject's weight, is from about 0.001 mg / kg to about 25 mg / kg. For example, the therapeutically effective dose of a non-naturally occurring melanocortin analogue, based on the subject's weight, is from about 0.001 mg / kg to about 25 mg / kg, from about 0.005 mg / kg to about 20 mg / kg, from about 0.01 mg / kg to about 15 mg / kg, from about 0.05 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 5 mg / kg, or from about 0.5 mg / kg to about 1 mg / kg.

[1251] In some embodiments, the therapeutically effective amount of a non-naturally occurring melanocortin analogue, depending on the subject's weight, is at least 0.001 mg / kg to at least 25 mg / kg. For example, the therapeutically effective amount of a non-naturally occurring melanocortin analogue, depending on the subject's weight, is at least 0.001 mg / kg to at least 25 mg / kg, at least 0.005 mg / kg to at least 20 mg / kg, at least 0.01 mg / kg to at least 15 mg / kg, at least 0.05 mg / kg to at least 10 mg / kg, at least 0.1 mg / kg to at least 5 mg / kg, or at least 0.5 mg / kg to at least 1 mg / kg.

[1252] In some embodiments, the therapeutically effective amount of a non-naturally occurring melanocortin analogue, depending on the subject's weight, is at least about 0.001 mg / kg to at least about 25 mg / kg. For example, the therapeutically effective amount of a non-naturally occurring melanocortin analogue, depending on the subject's weight, is at least about 0.001 mg / kg to at least about 25 mg / kg, at least about 0.005 mg / kg to at least about 20 mg / kg, at least about 0.01 mg / kg to at least about 15 mg / kg, at least about 0.05 mg / kg to at least about 10 mg / kg, at least about 0.1 mg / kg to at least about 5 mg / kg, or at least about 0.5 mg / kg to at least about 1 mg / kg.

[1253] In some embodiments, the therapeutically effective dose of a non-naturally occurring melanocortin analogue, depending on the subject's weight, is from about 0.5 mg / kg to about 10 mg / kg. For example, the therapeutically effective dose of a non-naturally occurring melanocortin analogue, depending on the subject's weight, is from about 0.5 mg / kg to about 10 mg / kg, from about 0.75 mg / kg to about 9 mg / kg, from about 1 mg / kg to about 8 mg / kg, from about 1.5 mg / kg to about 7 mg / kg, from about 2 mg / kg to about 6 mg / kg, or from about 3 mg / kg to about 5 mg / kg.

[1254] In some embodiments, the therapeutically effective dose of a non-naturally occurring melanocortin analogue is at least 0.5 mg / kg to at least 10 mg / kg, depending on the subject's weight. For example, the therapeutically effective dose of a non-naturally occurring melanocortin analogue is at least 0.5 mg / kg to at least 10 mg / kg, at least 0.75 mg / kg to at least 9 mg / kg, at least 1 mg / kg to at least 8 mg / kg, at least 1.5 mg / kg to at least 7 mg / kg, at least 2 mg / kg to at least 6 mg / kg, or at least 3 mg / kg to at least 5 mg / kg, depending on the subject's weight.

[1255] In some embodiments, the therapeutically effective amount of a non-naturally occurring melanocortin analogue, depending on the subject's weight, is at least about 0.5 mg / kg to at least about 10 mg / kg. For example, the therapeutically effective amount of a non-naturally occurring melanocortin analogue, depending on the subject's weight, is at least about 0.5 mg / kg to at least about 10 mg / kg, at least about 0.75 mg / kg to at least about 9 mg / kg, at least about 1 mg / kg to at least about 8 mg / kg, at least about 1.5 mg / kg to at least about 7 mg / kg, at least about 2 mg / kg to at least about 6 mg / kg, or at least about 3 mg / kg to at least about 5 mg / kg.

[1256] In some embodiments, the pharmaceutical composition is administered parenterally (e.g., subcutaneously) at a therapeutically effective dose of a non-naturally occurring melanocortin analogue, wherein the therapeutically effective dose is about 0.001 nmol, about 0.005 nmol, about 0.01 nmol, about 0.02 nmol, about 0.03 nmol, about 0.04 nmol, about 0.05 nmol, about 0.06 nmol, about 0.07 nmol, about 0.08 nmol, about 0.09 nmol, about 0.1 nmol, about 0.2 nmol, about 0.3 nmol, about 0.4 nmol, about 0.5 nmol, about 0.6 nmol, about 0.7 nmol, about 0.8 nmol, or about 0.9 nmol. Approximately 1.0 nmol, approximately 1.1 nmol, approximately 1.2 nmol, approximately 1.3 nmol, approximately 1.4 nmol, approximately 1.5 nmol, approximately 1.6 nmol, approximately 1.7 nmol, approximately 1.8 nmol, approximately 1.9 nmol, approximately 2 nmol, approximately 3 nmol, approximately 4 nmol, approximately 5 nmol, approximately 6 nmol, approximately 7 nmol, approximately 8 nmol, approximately 9 nmol, approximately 10 nmol, approximately 11 nmol, approximately 12 nmol, approximately 13 nmol, approximately 14 nmol, approximately 15 nmol, approximately 16 nmol, approximately 17 nmol, approximately 18 nmol, approximately 19 nmol, approximately 20 nmol, approximately 21 nmol, approximately 22 nmol 1. Approximately 23 nmol, approximately 24 nmol, approximately 25 nmol, approximately 26 nmol, approximately 27 nmol, approximately 28 nmol, approximately 29 nmol, approximately 30 nmol, approximately 31 nmol, approximately 32 nmol, approximately 33 nmol, approximately 34 nmol, approximately 35 nmol, approximately 36 nmol, approximately 37 nmol, approximately 38 nmol, approximately 39 nmol, approximately 40 nmol, approximately 41 nmol, approximately 42 nmol, approximately 43 nmol, approximately 44 nmol, approximately 45 nmol, approximately 46 nmol, approximately 47 nmol, approximately 48 nmol, approximately 49 nmol, approximately 50 nmol, approximately 51 nmol, approximately 52 nmol, approximately 53 nmol Approximately 54 nmol, approximately 55 nmol, approximately 56 nmol, approximately 57 nmol, approximately 58 nmol, approximately 59 nmol, approximately 60 nmol, approximately 61 nmol, approximately 62 nmol, approximately 63 nmol, approximately 64 nmol, approximately 65 nmol, approximately 66 nmol, approximately 67 nmol, approximately 68 nmol, approximately 69 nmol, approximately 70 nmol, approximately 61 nmol, approximately 72 nmol, approximately 73 nmol, approximately 74 nmol, approximately 75 nmol, approximately 76 nmol, approximately 77 nmol, approximately 78 nmol, approximately 79 nmol, approximately 80 nmol, approximately 81 nmol, approximately 82 nmol, approximately 83 nmol, approximately 84 nmol.Approximately 85 nmol, approximately 86 nmol, approximately 87 nmol, approximately 88 nmol, approximately 89 nmol, approximately 90 nmol, approximately 91 nmol, approximately 92 nmol, approximately 93 nmol, approximately 94 nmol, approximately 95 nmol, approximately 96 nmol, approximately 97 nmol, approximately 98 nmol, approximately 99 nmol, approximately 100 nmol, approximately 110 nmol, approximately 120 nmol, approximately 130 nmol, approximately 140 nmol, approximately 150 nmol, approximately 160 nmol, approximately 170 nmol, approximately 180 nmol, approximately 190 nmol, approximately 200 nmol, approximately 210 nmol, approximately 220 nmol 1, approximately 230 nmol, approximately 240 nmol, approximately 250 nmol, approximately 260 nmol, approximately 270 nmol, approximately 280 nmol, approximately 290 nmol, approximately 300 nmol, approximately 310 nmol, approximately 320 nmol, approximately 330 nmol, approximately 340 nmol, approximately 350 nmol, approximately 360 nmol, approximately 370 nmol, approximately 380 nmol, approximately 390 nmol, approximately 400 nmol, approximately 410 nmol, approximately 420 nmol, approximately 430 nmol, approximately 440 nmol, approximately 450 nmol, approximately 460 nmol, approximately 470 nmol, approximately 480 nmol, Approximately 490 nmol, approximately 500 nmol, approximately 510 nmol, approximately 520 nmol, approximately 530 nmol, approximately 540 nmol, approximately 550 nmol, approximately 660 nmol, approximately 770 nmol, approximately 880 nmol, approximately 990 nmol, approximately 600 nmol, approximately 610 nmol, approximately 620 nmol, approximately 630 nmol, approximately 640 nmol, approximately 650 nmol, approximately 660 nmol, approximately 670 nmol, approximately 680 nmol, approximately 690 nmol, approximately 700 nmol, approximately 710 nmol, approximately 720 nmol, approximately 730 nmol, approximately 740 nmol, approximately 7 50 nmol, approximately 760 nmol, approximately 770 nmol, approximately 780 nmol, approximately 790 nmol, approximately 800 nmol, approximately 810 nmol, approximately 820 nmol, approximately 830 nmol, approximately 840 nmol, approximately 850 nmol, approximately 860 nmol, approximately 870 nmol, approximately 880 nmol, approximately 890 nmol, approximately 900 nmol, approximately 910 nmol, approximately 920 nmol, approximately 930 nmol, approximately 940 nmol, approximately 950 nmol, approximately 960 nmol, approximately 970 nmol, approximately 980 nmol, approximately 990 nmol, approximately 1000 nmol or higher.

[1257] In some embodiments, the pharmaceutical composition is administered parenterally (e.g., subcutaneously) at a therapeutically effective dose of a non-naturally occurring melanocortin analogue, wherein the therapeutically effective dose is at least 0.001 nmol, at least 0.005 nmol, at least 0.01 nmol, at least 0.02 nmol, at least 0.03 nmol, at least 0.04 nmol, at least 0.05 nmol, at least 0.06 nmol, at least 0.07 nmol, at least 0.08 nmol, at least 0.09 nmol, at least 0.1 nmol, at least 0.2 nmol, at least 0.3 nmol, at least 0.4 nmol, at least 0.5 nmol, at least 0.6 nmol, at least 0.7 nmol, to... At least 0.8 nmol, at least 0.9 nmol, at least 1.0 nmol, at least 1.1 nmol, at least 1.2 nmol, at least 1.3 nmol, at least 1.4 nmol, at least 1.5 nmol, at least 1.6 nmol, at least 1.7 nmol, at least 1.8 nmol, at least 1.9 nmol, at least 2 nmol, at least 3 nmol, at least 4 nmol, at least 5 nmol, at least 6 nmol, at least 7 nmol, at least 8 nmol, at least 9 nmol, at least 10 nmol, at least 11 nmol, at least 12 nmol, at least 13 nmol, at least 14 nmol, at least 15 nmol, at least 16 nmol, at least 17 nmol, at least 18 nmol, at least 19 nmol, at least 20 nmol, at least 21 nmol, at least 22 nmol, at least 23 nmol, at least 24 nmol, at least 25 nmol, at least 26 nmol, at least 27 nmol, at least 28 nmol, at least 29 nmol, at least 30 nmol, at least 31 nmol, at least 32 nmol, at least 33 nmol, at least 34 nmol, at least 35 nmol, at least 36 nmol, at least 37 nmol, at least 38 nmol, at least 39 nmol, at least 40 nmol, at least 41 nmol, at least 42 nmol, at least 43 nmol, at least 44 nmol, at least 45 nmol, at least 46 nmol, at least 47 nmol, at least 48 nmol, at least 49 nmol, at least 50 nmol, at least 51 nmol, at least 52 nmol, at least 53 nmol, at least 54 nmol, at least 55 nmol, at least 56 nmol, at least 57 nmol, at least 58 nmol, at least 59 nmol, at least 60 nmol, at least 61 nmol, at least 62 nmol, at least 63 nmol, at least 64 nmol, at least 65 nmol, at least 66 nmol, at least 67 nmol, at least 68 nmol, at least 69 nmol, at least 70 nmol, at least 61 nmol, at least 72 nmol.At least 73 nmol, at least 74 nmol, at least 75 nmol, at least 76 nmol, at least 77 nmol, at least 78 nmol, at least 79 nmol, at least 80 nmol, at least 81 nmol, at least 82 nmol, at least 83 nmol, at least 84 nmol, at least 85 nmol, at least 86 nmol, at least 87 nmol, at least 88 nmol, at least 89 nmol, at least 90 nmol, at least 91 nmol, at least 92 nmol, at least 93 nmol, at least 94 nmol, at least 95 nmol, at least 96 nmol, at least 97 nmol, at least 98 nmol, at least 99 nmol, at least 100 nmol, at least 110 nmol, at least 120 nmol, at least 130 nmol, at least 140 nmol, at least 150 nmol, at least 160 nmol, at least 170 nmol, at least 180 nmol, at least 190 nmol, at least 200 nmol, at least 210 nmol, at least 220 nmol, at least 230 nmol, at least 240 nmol, at least 250 nmol, at least 260 nmol, at least 270 nmol, at least 280 nmol, at least 290 nmol, at least 300 nmol, at least 310 nmol, at least 320 nmol, at least 330 nmol, at least 340 nmol, at least 3 50 nmol, at least 360 nmol, at least 370 nmol, at least 380 nmol, at least 390 nmol, at least 400 nmol, at least 410 nmol, at least 420 nmol, at least 430 nmol, at least 440 nmol, at least 450 nmol, at least 460 nmol, at least 470 nmol, at least 480 nmol, at least 490 nmol, at least 500 nmol, at least 510 nmol, at least 520 nmol, at least 530 nmol, at least 540 nmol, at least 550 nmol, at least 660 nmol, at least 770 nmol, at least 880 nmol, at least 990 nmol, to At least 600 nmol, at least 610 nmol, at least 620 nmol, at least 630 nmol, at least 640 nmol, at least 650 nmol, at least 660 nmol, at least 670 nmol, at least 680 nmol, at least 690 nmol, at least 700 nmol, at least 710 nmol, at least 720 nmol, at least 730 nmol, at least 740 nmol, at least 750 nmol, at least 760 nmol, at least 770 nmol, at least 780 nmol, at least 790 nmol, at least 800 nmol, at least 810 nmol, at least 820 nmol, at least 830 nmol, at least 840 nmol.At least 850 nmol, at least 860 nmol, at least 870 nmol, at least 880 nmol, at least 890 nmol, at least 900 nmol, at least 910 nmol, at least 920 nmol, at least 930 nmol, at least 940 nmol, at least 950 nmol, at least 960 nmol, at least 970 nmol, at least 980 nmol, at least 990 nmol, at least 1000 nmol or higher.

[1258] In some embodiments, the pharmaceutical composition is administered parenterally (e.g., subcutaneously) at a therapeutically effective dose of a non-naturally occurring melanocortin analogue, wherein the therapeutically effective dose is at least about 0.001 nmol, at least about 0.005 nmol, at least about 0.01 nmol, at least about 0.02 nmol, at least about 0.03 nmol, at least about 0.04 nmol, at least about 0.05 nmol, at least about 0.06 nmol, at least about 0.07 nmol, at least about 0.08 nmol, at least about 0.09 nmol, at least about 0.1 nmol, at least about 0.2 nmol, at least about 0.3 nmol, at least about 0.4 nmol, at least about 0.5 nmol, or at least about 0. 6 nmol, at least about 0.7 nmol, at least about 0.8 nmol, at least about 0.9 nmol, at least about 1.0 nmol, at least about 1.1 nmol, at least about 1.2 nmol, at least about 1.3 nmol, at least about 1.4 nmol, at least about 1.5 nmol, at least about 1.6 nmol, at least about 1.7 nmol, at least about 1.8 nmol, at least about 1.9 nmol, at least about 2 nmol, at least about 3 nmol, at least about 4 nmol, at least about 5 nmol, at least about 6 nmol, at least about 7 nmol, at least about 8 nmol, at least about 9 nmol, at least about 10 nmol, at least about 11 nmol, at least about 12 nmol At least approximately 13 nmol, at least approximately 14 nmol, at least approximately 15 nmol, at least approximately 16 nmol, at least approximately 17 nmol, at least approximately 18 nmol, at least approximately 19 nmol, at least approximately 20 nmol, at least approximately 21 nmol, at least approximately 22 nmol, at least approximately 23 nmol, at least approximately 24 nmol, at least approximately 25 nmol, at least approximately 26 nmol, at least approximately 27 nmol, at least approximately 28 nmol, at least approximately 29 nmol, at least approximately 30 nmol, at least approximately 31 nmol, at least approximately 32 nmol, at least approximately 33 nmol, at least approximately 34 nmol, at least approximately 35 nmol, at least approximately 36 nmol, at least approximately 37 nmol At least approximately 38 nmol, at least approximately 39 nmol, at least approximately 40 nmol, at least approximately 41 nmol, at least approximately 42 nmol, at least approximately 43 nmol, at least approximately 44 nmol, at least approximately 45 nmol, at least approximately 46 nmol, at least approximately 47 nmol, at least approximately 48 nmol, at least approximately 49 nmol, at least approximately 50 nmol, at least approximately 51 nmol, at least approximately 52 nmol, at least approximately 53 nmol, at least approximately 54 nmol, at least approximately 55 nmol, at least approximately 56 nmol, at least approximately 57 nmol, at least approximately 58 nmol, at least approximately 59 nmol, at least approximately 60 nmol, at least approximately 61 nmol, at least approximately 62 nmol.At least approximately 63 nmol, at least approximately 64 nmol, at least approximately 65 nmol, at least approximately 66 nmol, at least approximately 67 nmol, at least approximately 68 nmol, at least approximately 69 nmol, at least approximately 70 nmol, at least approximately 61 nmol, at least approximately 72 nmol, at least approximately 73 nmol, at least approximately 74 nmol, at least approximately 75 nmol, at least approximately 76 nmol, at least approximately 77 nmol, at least approximately 78 nmol, at least approximately 79 nmol, at least approximately 80 nmol, at least approximately 81 nmol, at least approximately 82 nmol, at least approximately 83 nmol, at least approximately 84 nmol, at least approximately 85 nmol, at least approximately 86 nmol, at least approximately 87 nmol At least approximately 88 nmol, at least approximately 89 nmol, at least approximately 90 nmol, at least approximately 91 nmol, at least approximately 92 nmol, at least approximately 93 nmol, at least approximately 94 nmol, at least approximately 95 nmol, at least approximately 96 nmol, at least approximately 97 nmol, at least approximately 98 nmol, at least approximately 99 nmol, at least approximately 100 nmol, at least approximately 110 nmol, at least approximately 120 nmol, at least approximately 130 nmol, at least approximately 140 nmol, at least approximately 150 nmol, at least approximately 160 nmol, at least approximately 170 nmol, at least approximately 180 nmol, at least approximately 190 nmol, at least approximately 200 nmol, at least approximately 210 nmol mol, at least about 220 nmol, at least about 230 nmol, at least about 240 nmol, at least about 250 nmol, at least about 260 nmol, at least about 270 nmol, at least about 280 nmol, at least about 290 nmol, at least about 300 nmol, at least about 310 nmol, at least about 320 nmol, at least about 330 nmol, at least about 340 nmol, at least about 350 nmol, at least about 360 nmol, at least about 370 nmol, at least about 380 nmol, at least about 390 nmol, at least about 400 nmol, at least about 410 nmol, at least about 420 nmol, at least about 430 nmol, at least about 440 nmol, at least about 450 nmol, at least about 460 nmol, at least about 470 nmol, at least about 480 nmol, at least about 490 nmol, at least about 500 nmol, at least about 510 nmol, at least about 520 nmol, at least about 530 nmol, at least about 540 nmol, at least about 550 nmol, at least about 660 nmol, at least about 770 nmol, at least about 880 nmol, at least about 990 nmol, at least about 600 nmol, at least about 610 nmol, at least about 620 nmol, at least about 630 nmol, at least about 640 nmol, at least about 650 nmol, at least about 660 nmol.At least approximately 670 nmol, at least approximately 680 nmol, at least approximately 690 nmol, at least approximately 700 nmol, at least approximately 710 nmol, at least approximately 720 nmol, at least approximately 730 nmol, at least approximately 740 nmol, at least approximately 750 nmol, at least approximately 760 nmol, at least approximately 770 nmol, at least approximately 780 nmol, at least approximately 790 nmol, at least approximately 800 nmol, at least approximately 810 nmol, at least approximately 820 nmol, at least approximately 830 nmol, at least Approximately 840 nmol, at least approximately 850 nmol, at least approximately 860 nmol, at least approximately 870 nmol, at least approximately 880 nmol, at least approximately 890 nmol, at least approximately 900 nmol, at least approximately 910 nmol, at least approximately 920 nmol, at least approximately 930 nmol, at least approximately 940 nmol, at least approximately 950 nmol, at least approximately 960 nmol, at least approximately 970 nmol, at least approximately 980 nmol, at least approximately 990 nmol, at least approximately 1000 nmol or higher.

[1259] In some embodiments, at least one individual dose of a non-naturally occurring melanocortin analogue is no more than about 1000 nmol, about 990 nmol, about 980 nmol, about 970 nmol, about 960 nmol, about 950 nmol, about 940 nmol, about 930 nmol, about 920 nmol, about 910 nmol, about 900 nmol, about 890 nmol, about 880 nmol, about 870 nmol, about 860 nmol, about 850 nmol, about 840 nmol, about 830 nmol, about 820 nmol, about 810 nmol, about 800 nmol, about 790 nmol, about 780 nmol, or about 770 nmol. ol, approximately 760 nmol, approximately 750 nmol, approximately 740 nmol, approximately 730 nmol, approximately 720 nmol, approximately 710 nmol, approximately 700 nmol, approximately 690 nmol, approximately 680 nmol, approximately 670 nmol, approximately 660 nmol, approximately 650 nmol, approximately 640 nmol, approximately 630 nmol, approximately 620 nmol, approximately 610 nmol, approximately 600 nmol, approximately 590 nmol, approximately 580 nmol, approximately 570 nmol, approximately 560 nmol, approximately 550 nmol, approximately 540 nmol, approximately 530 nmol, approximately 520 nmol, approximately 510 nmol, approximately 500 nmol, approximately 490 nmol, approximately 480 nmol, approximately 470 nmol, approximately 460 nmol, approximately 450 nmol, approximately 440 nmol, approximately 430 nmol, approximately 420 nmol, approximately 410 nmol, approximately 400 nmol, approximately 390 nmol, approximately 380 nmol, approximately 370 nmol, approximately 360 nmol, approximately 350 nmol, approximately 340 nmol, approximately 330 nmol, approximately 320 nmol, approximately 310 nmol, approximately 300 nmol, approximately 290 nmol, approximately 280 nmol, approximately 270 nmol, approximately 260 nmol, approximately 250 nmol, approximately 240 nmol, approximately 230 nmol, approximately 220 nmol, approximately 2 10 nmol, approximately 200 nmol, approximately 190 nmol, approximately 180 nmol, approximately 170 nmol, approximately 160 nmol, approximately 150 nmol, approximately 140 nmol, approximately 130 nmol, approximately 120 nmol, approximately 110 nmol, approximately 100 nmol, approximately 99 nmol, approximately 98 nmol, approximately 97 nmol, approximately 96 nmol, approximately 95 nmol, approximately 94 nmol, approximately 93 nmol, approximately 92 nmol, approximately 91 nmol, approximately 90 nmol, approximately 89 nmol, approximately 88 nmol, approximately 87 nmol, approximately 86 nmol, approximately 85 nmol, approximately 84 nmol, approximately 83 nmol, approximately 82 nmol,Approximately 81 nmol, approximately 80 nmol, approximately 79 nmol, approximately 78 nmol, approximately 77 nmol, approximately 76 nmol, approximately 75 nmol, approximately 74 nmol, approximately 73 nmol, approximately 72 nmol, approximately 71 nmol, approximately 70 nmol, approximately 69 nmol, approximately 68 nmol, approximately 67 nmol, approximately 66 nmol, approximately 65 nmol, approximately 64 nmol, approximately 63 nmol, approximately 62 nmol, approximately 61 nmol, approximately 60 nmol, approximately 59 nmol, approximately 58 nmol, approximately 5 7 nmol, approximately 56 nmol, approximately 95 nmol, approximately 54 nmol, approximately 53 nmol, approximately 52 nmol, approximately 51 nmol, approximately 50 nmol, approximately 49 nmol, approximately 48 nmol, approximately 47 nmol, approximately 46 nmol, approximately 45 nmol, approximately 44 nmol, approximately 43 nmol, approximately 42 nmol, approximately 41 nmol, approximately 40 nmol, approximately 39 nmol, approximately 38 nmol, approximately 37 nmol, approximately 36 nmol, approximately 35 nmol, approximately 34 nmol, approximately 33 nmol mol, approximately 32 nmol, approximately 31 nmol, approximately 30 nmol, approximately 29 nmol, approximately 28 nmol, approximately 27 nmol, approximately 26 nmol, approximately 25 nmol, approximately 24 nmol, approximately 23 nmol, approximately 22 nmol, approximately 21 nmol, approximately 20 nmol, approximately 19 nmol, approximately 18 nmol, approximately 17 nmol, approximately 16 nmol, approximately 15 nmol, approximately 94 nmol, approximately 13 nmol, approximately 12 nmol, approximately 11 nmol, approximately 10 nmol, approximately 9 nmol Approximately 8 nmol, approximately 7 nmol, approximately 6 nmol, approximately 5 nmol, approximately 4 nmol, approximately 3 nmol, approximately 2 nmol, approximately 1 nmol, approximately 0.9 nmol, approximately 0.8 nmol, approximately 0.7 nmol, approximately 0.6 nmol, approximately 0.5 nmol, approximately 0.4 nmol, approximately 0.3 nmol, approximately 0.2 nmol, approximately 0.1 nmol, approximately 0.05 nmol, approximately 0.01 nmol, approximately 0.005 nmol, approximately 0.001 nmol, or less than approximately 0.001 nmol.

[1260] In some embodiments, at least one individual dose of a non-naturally occurring melanocortin analogue is no more than at least 1000 nmol, at least 990 nmol, at least 980 nmol, at least 970 nmol, at least 960 nmol, at least 950 nmol, at least 940 nmol, at least 930 nmol, at least 920 nmol, at least 910 nmol, at least 900 nmol, at least 890 nmol, at least 880 nmol, at least 870 nmol, at least 860 nmol, at least 850 nmol, at least 840 nmol, at least 830 nmol, at least 820 nmol, at least 810 nmol, at least 800 nmol, at least 79 0 nmol, at least 780 nmol, at least 770 nmol, at least 760 nmol, at least 750 nmol, at least 740 nmol, at least 730 nmol, at least 720 nmol, at least 710 nmol, at least 700 nmol, at least 690 nmol, at least 680 nmol, at least 670 nmol, at least 660 nmol, at least 650 nmol, at least 640 nmol, at least 630 nmol, at least 620 nmol, at least 610 nmol, at least 600 nmol, at least 590 nmol, at least 580 nmol, at least 570 nmol, at least 560 nmol, at least 550 nmol, at least 54 0 nmol, at least 530 nmol, at least 520 nmol, at least 510 nmol, at least 500 nmol, at least 490 nmol, at least 480 nmol, at least 470 nmol, at least 460 nmol, at least 450 nmol, at least 440 nmol, at least 430 nmol, at least 420 nmol, at least 410 nmol, at least 400 nmol, at least 390 nmol, at least 380 nmol, at least 370 nmol, at least 360 nmol, at least 350 nmol, at least 340 nmol, at least 330 nmol, at least 320 nmol, at least 310 nmol, at least 300 nmol, at least 29 0 nmol, at least 280 nmol, at least 270 nmol, at least 260 nmol, at least 250 nmol, at least 240 nmol, at least 230 nmol, at least 220 nmol, at least 210 nmol, at least 200 nmol, at least 190 nmol, at least 180 nmol, at least 170 nmol, at least 160 nmol, at least 150 nmol, at least 140 nmol, at least 130 nmol, at least 120 nmol, at least 110 nmol, at least 100 nmol, at least 99 nmol, at least 98 nmol, at least 97 nmol, at least 96 nmol, at least 95 nmol, at least 94 nmolAt least 93 nmol, at least 92 nmol, at least 91 nmol, at least 90 nmol, at least 89 nmol, at least 88 nmol, at least 87 nmol, at least 86 nmol, at least 85 nmol, at least 84 nmol, at least 83 nmol, at least 82 nmol, at least 81 nmol, at least 80 nmol, at least 79 nmol, at least 78 nmol, at least 77 nmol, at least 76 nmol, at least 75 nmol, at least 74 nmol, at least 73 nmol, at least 72 nmol, at least 71 nmol, at least 70 nmol, at least 69 nmol, at least 68 nmol, at least 67 nmol, at least 66 nmol, at least 65 nmol, at least 64 nmol, at least 63 nmol, at least 62 nmol, at least 61 nmol, at least 60 nmol, at least 59 nmol, at least 58 nmol, at least 57 nmol, at least 56 nmol, at least 95 nmol, at least 54 nmol, at least 53 nmol, at least 52 nmol, at least 51 nmol, at least 50 nmol, at least 49 nmol, at least 48 nmol, at least 47 nmol, at least 46 nmol, at least 45 nmol, at least 44 nmol, at least 43 nmol, at least 42 nmol, at least 41 nmol, at least 40 nmol, at least 39 nmol, at least 38 nmol, at least 37 nmol, at least 36 nmol, at least 35 nmol, at least 34 nmol, at least 33 nmol, at least 32 nmol, at least 31 nmol, at least 30 nmol, at least 29 nmol, at least 28 nmol, at least 27 nmol, at least 26 nmol, at least 25 nmol, at least 24 nmol, at least 23 nmol, at least 22 nmol, at least 21 nmol, at least 20 nmol, at least 19 nmol, at least 18 nmol, at least 17 nmol, at least 16 nmol, at least 15 nmol, at least 94 nmol, at least 13 nmol, at least 12 nmol ol, at least 11 nmol, at least 10 nmol, at least 9 nmol, at least 8 nmol, at least 7 nmol, at least 6, at least nmol, at least 5 nmol, at least 4 nmol, at least 3 nmol, at least 2 nmol, at least 1 nmol, at least 0.9 nmol, at least 0.8 nmol, at least 0.7 nmol, at least 0.6 nmol, at least 0.5 nmol, at least 0.4 nmol, at least 0.3 nmol, at least 0.2 nmol, at least 0.1 nmol, at least 0.05 nmol, at least 0.01 nmol, at least 0.005 nmol, at least 0.001 nmol, or less than at least 0.001 nmol.

[1261] In some embodiments, at least one individual dose of a non-naturally occurring melanocortin analogue is no more than at least about 1000 nmol, at least about 990 nmol, at least about 980 nmol, at least about 970 nmol, at least about 960 nmol, at least about 950 nmol, at least about 940 nmol, at least about 930 nmol, at least about 920 nmol, at least about 910 nmol, at least about 900 nmol, at least about 890 nmol, at least about 880 nmol, at least about 870 nmol, at least about 860 nmol, at least about 850 nmol, at least about 840 nmol, at least about 830 nmol, at least about 820 nmol, at least about 810 nmol, at least about 800 nmol, at least about 790 nmol, at least about 780 nmol, at least about 770 nmol, at least about 760 nmol, at least about 750 nmol, at least about 740 nmol, at least about 730 nmol, at least about 720 nmol, at least about 710 nmol, at least about 700 nmol, at least about 690 nmol, at least about 680 nmol, at least about 670 nmol, at least about 660 nmol, at least about 650 nmol, at least about 640 nmol, at least about 630 nmol, at least about 620 nmol, at least about 610 nmol, at least about 600 nmol, at least about 590 nmol l, at least approximately 580 nmol, at least approximately 570 nmol, at least approximately 560 nmol, at least approximately 550 nmol, at least approximately 540 nmol, at least approximately 530 nmol, at least approximately 520 nmol, at least approximately 510 nmol, at least approximately 500 nmol, at least approximately 490 nmol, at least approximately 480 nmol, at least approximately 470 nmol, at least approximately 460 nmol, at least approximately 450 nmol, at least approximately 440 nmol, at least approximately 430 nmol, at least approximately 420 nmol, at least approximately 410 nmol, at least approximately 400 nmol, at least approximately 390 nmol, at least approximately 380 nmol, at least approximately 370 nmol, at least approximately 3 60 nmol, at least about 350 nmol, at least about 340 nmol, at least about 330 nmol, at least about 320 nmol, at least about 310 nmol, at least about 300 nmol, at least about 290 nmol, at least about 280 nmol, at least about 270 nmol, at least about 260 nmol, at least about 250 nmol, at least about 240 nmol, at least about 230 nmol, at least about 220 nmol, at least about 210 nmol, at least about 200 nmol, at least about 190 nmol, at least about 180 nmol, at least about 170 nmol, at least about 160 nmol, at least about 150 nmol, at least about 140 nmol.At least approximately 130 nmol, at least approximately 120 nmol, at least approximately 110 nmol, at least approximately 100 nmol, at least approximately 99 nmol, at least approximately 98 nmol, at least approximately 97 nmol, at least approximately 96 nmol, at least approximately 95 nmol, at least approximately 94 nmol, at least approximately 93 nmol, at least approximately 92 nmol, at least approximately 91 nmol, at least approximately 90 nmol, at least approximately 89 nmol, at least approximately 88 nmol, at least approximately 87 nmol, at least approximately 86 nmol, at least approximately 85 nmol, at least approximately 84 nmol, at least approximately 83 nmol, at least approximately 82 nmol, at least approximately 81 nmol, at least approximately 80 nmol, at least approximately 7 9 nmol, at least about 78 nmol, at least about 77 nmol, at least about 76 nmol, at least about 75 nmol, at least about 74 nmol, at least about 73 nmol, at least about 72 nmol, at least about 71 nmol, at least about 70 nmol, at least about 69 nmol, at least about 68 nmol, at least about 67 nmol, at least about 66 nmol, at least about 65 nmol, at least about 64 nmol, at least about 63 nmol, at least about 62 nmol, at least about 61 nmol, at least about 60 nmol, at least about 59 nmol, at least about 58 nmol, at least about 57 nmol, at least about 56 nmol, at least about 95 nmol, at least Approximately 54 nmol, at least approximately 53 nmol, at least approximately 52 nmol, at least approximately 51 nmol, at least approximately 50 nmol, at least approximately 49 nmol, at least approximately 48 nmol, at least approximately 47 nmol, at least approximately 46 nmol, at least approximately 45 nmol, at least approximately 44 nmol, at least approximately 43 nmol, at least approximately 42 nmol, at least approximately 41 nmol, at least approximately 40 nmol, at least approximately 39 nmol, at least approximately 38 nmol, at least approximately 37 nmol, at least approximately 36 nmol, at least approximately 35 nmol, at least approximately 34 nmol, at least approximately 33 nmol, at least approximately 32 nmol, at least approximately 31 nmol, at least approximately 30 nmol. At least approximately 29 nmol, at least approximately 28 nmol, at least approximately 27 nmol, at least approximately 26 nmol, at least approximately 25 nmol, at least approximately 24 nmol, at least approximately 23 nmol, at least approximately 22 nmol, at least approximately 21 nmol, at least approximately 20 nmol, at least approximately 19 nmol, at least approximately 18 nmol, at least approximately 17 nmol, at least approximately 16 nmol, at least approximately 15 nmol, at least approximately 94 nmol, at least approximately 13 nmol, at least approximately 12 nmol, at least approximately 11 nmol, at least approximately 10 nmol, at least approximately 9 nmol, at least approximately 8 nmol, at least approximately 7 nmol, at least approximately 6, at least approximately nmol, at least approximately 5 nmol.At least about 4 nmol, at least about 3 nmol, at least about 2 nmol, at least about 1 nmol, at least about 0.9 nmol, at least about 0.8 nmol, at least about 0.7 nmol, at least about 0.6 nmol, at least about 0.5 nmol, at least about 0.4 nmol, at least about 0.3 nmol, at least about 0.2 nmol, at least about 0.1 nmol, at least about 0.05 nmol, at least about 0.01 nmol, at least about 0.005 nmol, at least about 0.001 nmol, or less than at least about 0.001 nmol.

[1262] In some embodiments, at least one individual dose of a non-naturally occurring melanocortin analogue is no more than about 1000 mg, about 990 mg, about 980 mg, about 970 mg, about 960 mg, about 950 mg, about 940 mg, about 930 mg, about 920 mg, about 910 mg, about 900 mg, about 890 mg, about 880 mg, about 870 mg, about 860 mg, about 850 mg, about 840 mg, about 830 mg, about 820 mg, about 810 mg, about 800 mg, about 790 mg, about 780 mg, about 770 mg, about 760 mg, about 750 mg, about 740 mg, about 730 mg, about 720 mg, about 710 mg, or about 70 mg. 0mg, approximately 690mg, approximately 680mg, approximately 670mg, approximately 660mg, approximately 650mg, approximately 640mg, approximately 630mg, approximately 620mg, approximately 610mg, approximately 600mg, approximately 590mg, approximately 580mg, approximately 570mg, approximately 560mg, approximately 550mg, approximately 540mg, approximately 530mg, approximately 520mg, approximately 510mg, approximately 500mg, approximately 490mg, approximately 480mg, approximately 470mg, approximately 460mg, approximately 450mg, approximately 440mg, approximately 430mg, approximately 420mg, approximately 410mg, approximately 400mg, approximately 390mg, approximately 380mg, approximately 370mg, approximately 360mg, approximately 350mg Approximately 340mg, approximately 330mg, approximately 320mg, approximately 310mg, approximately 300mg, approximately 290mg, approximately 280mg, approximately 270mg, approximately 260mg, approximately 250mg, approximately 240mg, approximately 230mg, approximately 220mg, approximately 210mg, approximately 200mg, approximately 190mg, approximately 180mg, approximately 170mg, approximately 160mg, approximately 150mg, approximately 140mg, approximately 130mg, approximately 120mg, approximately 110mg, approximately 100mg, approximately 99mg, approximately 98mg, approximately 97mg, approximately 96mg, approximately 95mg, approximately 94mg, approximately 93mg, approximately 92mg, approximately 91mg, approximately 90mg, approximately 89mg, approximately 88mg, approximately 8 7mg, approximately 86mg, approximately 85mg, approximately 84mg, approximately 83mg, approximately 82mg, approximately 81mg, approximately 80mg, approximately 79mg, approximately 78mg, approximately 77mg, approximately 76mg, approximately 75mg, approximately 74mg, approximately 73mg, approximately 72mg, approximately 71mg, approximately 70mg, approximately 69mg, approximately 68mg, approximately 67mg, approximately 66mg, approximately 65mg, approximately 64mg, approximately 63mg, approximately 62mg, approximately 61mg, approximately 60mg, approximately 59mg, approximately 58mg, approximately 57mg, approximately 56mg, approximately 95mg, approximately 54mg, approximately 53mg, approximately 52mg, approximately 51mg, approximately 50mg, approximately 49mg, approximately 48mg, approximately 47mg, approximately 46mgApproximately 45mg, approximately 44mg, approximately 43mg, approximately 42mg, approximately 41mg, approximately 40mg, approximately 39mg, approximately 38mg, approximately 37mg, approximately 36mg, approximately 35mg, approximately 34mg, approximately 33mg, approximately 32mg, approximately 31mg, approximately 30mg, approximately 29mg, approximately 28mg, approximately 27mg, approximately 26mg, approximately 25mg, approximately 24mg, approximately 23mg, approximately 22mg, approximately 21mg, approximately 20mg, approximately 19mg, approximately 18mg, approximately 17mg, approximately 16mg. Approximately 15mg, approximately 94mg, approximately 13mg, approximately 12mg, approximately 11mg, approximately 10mg, approximately 9mg, approximately 8mg, approximately 7mg, approximately 6mg, approximately 5mg, approximately 4mg, approximately 3mg, approximately 2mg, approximately 1mg, approximately 0.9mg, approximately 0.8mg, approximately 0.7mg, approximately 0.6mg, approximately 0.5mg, approximately 0.4mg, approximately 0.3mg, approximately 0.2mg, approximately 0.1mg, approximately 0.05mg, approximately 0.01mg, approximately 0.005mg, or approximately 0.001mg.

[1263] In some embodiments, at least one individual dose of a non-naturally occurring melanocorticoid analogue is not more than at least 1000 mg, at least 990 mg, at least 980 mg, at least 970 mg, at least 960 mg, at least 950 mg, at least 940 mg, at least 930 mg, at least 920 mg, at least 910 mg, at least 900 mg, at least 890 mg, at least 880 mg, at least 870...

Claims

1. A method for stimulating the appetite and / or increasing the weight of a subject suffering from kidney disease and / or liver disease, the method comprising: The subject was administered a therapeutically effective amount of a non-naturally occurring melanocortin analogue, the non-naturally occurring melanocortin analogue comprising the sequence according to formula (I). X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I) wherein: R 1 is absent or selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), trans-4-guanidino-proline (trans Pro(guan)), cis-4-guanidino-proline (cis Pro(guan)), acetylated trans-4-guanidino-proline (Ac-trans Pro(guan)), acetylated cis-4-guanidino-proline (Ac-cis Pro(guan)), tyrosine, D-tyrosine, dimethyl tyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid; R 2 is absent or selected from the group consisting of proline, histidine, D-hydroxyproline (dHyp), trans-Pro(guan), cis-Pro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, leucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine; R 3 is absent or selected from the group consisting of histidine, L-proline, trans Pro(guan), cis Pro(guan), D-valine, glutamic acid, tryptophylarginine (Trp-Arg), glycine, D-leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazol-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), octahydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), and indoline-2-carboxylic acid (Ioc), R 4 is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, dBip, glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-iodo-D-phenylalanine (p(I)dPhe), p-fluoro-D-phenylalanine (p(F)dPhe), and p-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R 5 is absent or selected from the group consisting of: arginine, homoarginine, proline, trans Pro(guan), cis Pro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(I)dPhe; R 6 is absent or selected from the group consisting of L-tryptophan, D-phenylalanine, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(l'), Aba, Ata, D-tyrosine, Pen, dPen, and D-alanine; R 7 is absent or selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2'), and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R 8 is absent or lysine; R 9 to R 20 absent; X 1 none or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, beta-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine; X 2 is absent or is D-proline; X 3 absent; Y 1 is absent or selected from the group consisting of D-valine, D-tert-leucine, L-tert-leucine, norleucine, and D-proline; Y 2 is absent or selected from the group consisting of D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, and glycine; Y 3 is absent or selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine; Y 4 is absent or is D-aspartic acid or aspartic acid; Y 5 to Y 8 absent; The non-natural melanocortin analogue is optionally partially cyclized by selecting from the group consisting of: When R 1 is cysteine and R 7 is cysteine, R 1 is a disulfide bond between R 7 and R When R 1 is norleucine and R 7 is glutamic acid, R 1 is a lactam bridge between R 7 and R When R 1 or R 2 It is glutamic acid or aspartic acid and R 7 When it is lysine or Dap, R 1 or R 2 With R 7 The side-chain lactam bridges between them; When R 2 For lysine and R 7 When it is glutamic acid or aspartic acid, R 2 With R 7 The side-chain lactam bridges between them; When R 1 or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 or R 2 With R 8 The side-chain lactam bridges between them; The conditions are: when R 2 is dAsp, then R 7 is not dLys; when R 2 to R 4 is Asp-His-dNal(2'), Asp-Pro-dNal(2') or Asp-Pro-dPhe, then R 5 to R 7 is not Arg-Trp-Lys; When Y 1 is dPro, Y 2 is dVal and Y 3 is dAla to Y 8 is absent, then R 4 is not dNal(2') or R 4 is dNal(2') and the C-terminus is not modified; When R 3 For Aba, Ata, or Aia, R 6 When it is Aia, then R 4 Not dNal(2'), or R 4 For dNal(2') and R 5 Not for Arg; When R 4 When R is p(Cl)dPhe, then 3 Not Pro or His; When R 4 When p(I)dPhe is used, the non-natural melanocortin analogue is obtained through R. 1 With R 7 The side-chain lactam bridged cyclization between them, and R 2 and R 3 At least one of them is Pro; When Y 2 To Y 4 If it does not exist, then Y 1 It is absent or contains ortholeucine; When R 2 For Pro or Y 2 When it is Hyp, then R 3 Not for Pro; When R 3 R 5 or R 6 If it is not present, then the non-naturally occurring melanocortin analogue is obtained through R. 1 With R 7 The cyclization of lactams between them, or X 1 To X 2 It exists and is Ac-dVal-dPro; When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys or Cys-Pro-dNal(2')-Arg-Trp-Cys, then R 1 Not Ac-Nle or Y 1 To Y 2 Not dVal-dPro, dVal-dVal, or dPro-dPro; and When the aforementioned non-naturally occurring melanocortin analogue is administered via R 2 With R 8 When the lactam bridges between them are cyclized, Then R 3 Not His or Y 1 Not dVal.

2. The method of claim 1, wherein, if present, the N-terminus is modified with a functional group selected from the group consisting of: acyl groups, imine groups, amide groups, urea groups, carbamate groups, sulfonamide groups, and alkylamine groups.

3. The method of claim 2, wherein, if present, the N-terminus is modified with an acyl group.

4. The method according to claim 3, wherein the acyl group is an acetyl group.

5. The method according to claim 3, wherein the acyl group is a formyl group.

6. The method of claim 2, wherein, if present, the N-terminus is modified with an imine group.

7. The method of claim 2, wherein, if present, the N-terminus is modified with an amide group.

8. The method according to claim 7, wherein the amide group is a pyroglutamyl (pGlu) group.

9. The method of claim 7, wherein the amide group is derived from a fatty acid.

10. The method of claim 1, wherein, if present, the N-terminus is not modified.

11. The method of claim 1, wherein the C-terminus is modified with a functional group selected from the group consisting of amide groups, ester groups, and aldehyde groups.

12. The method of claim 11, wherein the C-terminus is modified with an amide group.

13. The method according to claim 12, wherein the amide group is a -NH alkylamide group or a -NH arylamide group.

14. The method according to claim 13, wherein the -NH arylamide group is a p-nitroaniline group or 7-amino-4-methylcoumarin.

15. The method of claim 11, wherein the C-terminus is modified with an ester group.

16. The method of claim 1, wherein the C-terminus is not modified.

17. The method of claim 1, wherein R 1 It does not exist, and R 2 It is D-aspartic acid.

18. The method of claim 17, wherein X 1 X 2 and X 3 It does not exist.

19. The method of claim 1, wherein R 4 It is D-Nal(2').

20. The method of claim 1, wherein Y 3 To Y 8 It does not exist.

21. The method of claim 20, wherein: Y 1 It is D-valine and Y 2 It is D-proline; or Y 1 It is D-proline and Y 2 It is D-valine.

22. The method of claim 1, wherein Y 3 Existence and Y 4 To Y 8 It does not exist.

23. The method according to claim 22, wherein: Y 1 It is either D-valine or D-proline; Y 2 It is D-valine or D-proline; and / or Y 3 It is either D-valine or D-proline.

24. The method of claim 22, wherein: Y 1 For D-valine, Y 2 It is D-valine and Y 3 It is D-proline; Y 1 For D-proline, Y 2 It is D-valine and Y 3 It is D-valine; Y 1 For D-valine, Y 2 It is D-proline and Y 3 It is D-valine; or Y 1 For D-proline, Y 2 It is D-valine and Y 3 It is D-proline.

25. The method of claim 1, wherein Y 3 and Y 4 It exists, and Y 5 To Y 8 It does not exist.

26. The method of claim 25, wherein: Y 1 It is either D-valine or D-proline; Y 2 It is either D-valine or D-proline; Y 3 It is D-valine or D-proline; and / or Y 4 It is either D-valine or D-proline.

27. The method of claim 25, wherein: Y 1 For D-valine, Y 2 For D-valine, Y 3 It is D-valine and Y 4 It is D-proline; Y 1 For D-proline, Y 2 For D-valine, Y 3 It is D-valine and Y 4 It is D-valine; Y 1 For D-valine, Y 2 For D-proline, Y 3 It is D-valine and Y 4 It is D-valine; Y 1 For D-valine, Y 2 For D-valine, Y 3 It is D-proline and Y 4 It is D-valine; or Y 1 For D-valine, Y 2 For D-proline, Y 3 It is D-valine and Y 4 It is D-proline.

28. The method of claim 1, wherein R 1 R 2 and R 7 Existence and R 8 To R 20 It does not exist, and the sequence of equation (I) is passed through R. 2 and R 7 Cyclation via lactam bonds.

29. The method of claim 1, wherein R 1 R 2 R 7 and R 8 Existence and R 9 To R 20 It does not exist, and the sequence of equation (I) is passed through R. 2 and R 8 Cyclation via lactam bonds.

30. The method according to claim 29, wherein: R 1 It is acetylated leucine; R 2 It is aspartic acid; R 3 Choose the group consisting of the following: proline, hydroxyproline, D-hydroxyproline, phenylalanine, and histidine; R 4 For histidine or dNal(2'); R 5 For dNal(2') or arginine; R 6 Choose the group consisting of the following: arginine, D-tryptophan, and L-tryptophan; R 7 It is tryptophan or proline; R 8 It is lysine; Y 1 Choose the group consisting of: D-valine, D-leucine, and D-isoleucine; and / or Y 2 It is D-proline.

31. The method according to claim 29, wherein the sequence of formula (I) is Ac-Nle- c (Asp-Pro-His-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 10; D5), Where c represents through R 2 and R 8 Cyclation via lactam bonds.

32. The method according to claim 1, wherein the sequence of formula (I) is linear.

33. The method according to claim 32, wherein the sequence of formula (I) is Ac-Nle-Pro-dNal(2')-Arg-Trp-dVal-dPro-NH2 (SEQ ID NO:14).

34. The method according to claim 1, wherein the sequence of formula (I) is selected from the group consisting of: Ac-transPro(guan)-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:33); Ac-cis-Pro(guan)-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 34); dTyr-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 35); Tyr-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 36); Dmt-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 37); Ac-Glu-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 38); and Ac-Asn-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:39), Where c represents through R 2 and R 7 Cyclation via lactam bonds.

35. The method according to claim 1, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-dLeu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:82); Ac-Nle-c(Asp-dIle-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:83); Ac-Nle-c(Asp-dVal-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-c(Asp-Trp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:85); Ac-Nle-c(Asp-dTrp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Nle-c(Asp-transPro(guan)-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:87); Ac-Nle-c(Asp-cis-Pro(guan)-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:88); Ac-Nle-c(Asp-Val-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:89); Ac-Nle-c(Asp-Ile-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:90); Ac-Nle-c(Asp-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:91); Ac-Nle-c(Asp-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:92); Ac-Nle-c(Asp-Arg-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:93); Ac-Nle-c(Asp-dLeu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:94); Ac-Nle-c(Asp-dAla-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:95); and Ac-Nle-c(Asp-dMet-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:96), where c represents the result of passing through R 2 and R 7 Cyclation via lactam bonds.

36. The method according to claim 1, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2')-dHis-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 108); Ac-Nle-c(Asp-Pro-dNal(2')-dAla-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 109); Ac-Nle-c(Asp-Pro-dNal(2')-dAsp-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 110); and Ac-Nle-c(Asp-Pro-dNal(2')-dGlu-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:111), where c represents the expression via R 2 and R 7 Cyclation via lactam bonds.

37. The method according to claim 1, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dNal(1')-Lys)-dVal-dPro-NH2 (SEQ ID NO: 119); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dPhe-Lys)-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dNal(2')-Lys)-dVal-dPro-NH2 (SEQ ID NO: 121); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dTyr-Lys)-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dHis-Lys)-dVal-dPro-NH2 (SEQ ID NO: 123); and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dAla-Lys)-dVal-dPro-NH2(SEQ ID NO:124), where c represents the expression via R 2 and R 7 Cyclation via lactam bonds.

38. The method according to claim 1, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-OH (SEQ ID NO: 128); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dVal-dPro-NH2 (SEQ ID NO: 182); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dPro-NH2 (SEQ ID NO: 183); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dVal-NH2 (SEQ ID NO: 184); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dTle-NH2 (SEQ ID NO: 185); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dTle-dPro-NH2 (SEQ ID 8O:186); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dTle-dVal-NH2 (SEQ ID NO: 187); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dTle-NH2 (SEQ ID NO: 188); and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dTle-NH2(SEQ ID NO:189), where c represents the result of passing through R 2 and R 7 Cyclation via lactam bonds.

39. The method according to claim 1, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Che-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:212); Ac-Nle-c(Asp-Oic-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:213); Ac-Nle-c(Asp-Ioc-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:214); Ac-Nle-c(Asp-Tic-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:215); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO:216); Ac-Nle-c(Asp-His-dNal(2')-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:217); Ac-Nle-c(Asp-His-dNal(2')-trans-Pro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:218); Ac-Nle-c(Asp-His-dNal(2')-cis-Pro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:219); Ac-Nle-c(Asp-Pro-dNal(2')-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:220); Ac-Nle-c(Asp-Pro-dNal(2')-trans-Pro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:221); Ac-Nle-c(Asp-Pro-dNal(2')-cis-Pro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:222); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Aba-Lys)-dVal-dPro-NH2 (SEQ ID NO:223); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Ata-Lys)-dVal-dPro-NH2 (SEQ ID NO:224); Ac-Nle-c(Asp-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:225); Ac-Nle-c(Asp-Glu-dNal(2')-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO: 226); Ac-Nle-c(Asp-Pro-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 227); Ac-Nle-c(Asp-Pro-Glu-dNal(2')-Arg-Trp-Gly-Lys)-dVal-dPro-NH2(SEQ ID NO:228); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dVal-dPro-NH2(SEQ ID NO:229); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dPro-dPro-Lys-Asp-NH2 (SEQ IDNO: 230); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dPro-dPro-dLys-dAsp-NH2 (SEQ IDNO: 231); Ac-Glu-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO: 232); and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO: 233), Where c represents through R 2 and R 7 Cyclation via lactam bonds.

40. The method according to claim 1, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Glu-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 234); Ac-Nle-c(Asp-Glu-His-dNal(2')-Arg-Trp-Gly-Lys)-dVal-dPro-NH2(SEQ ID NO:235); Ac-Nle-c(Asp-dAla-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:236); Ac-Arg-c(Asp-dAla-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 237); Ac-Arg-c(Asp-dAla-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:238); Ac-Arg-c(Cys-dAla-His-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:239); Ac-dArg-c(Asp-dAla-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:240);Ac-Arg-c(Asp-dAla-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:241); Ac-dArg-c(Asp-dAla-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:242); Ac-Nle-c(Asp-Ala-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:243); Ac-Arg-c(Asp-Ala-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:244); Ac-dArg-c(Asp-Ala-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:245); Ac-Nle-c(Asp-Trp-Arg-dNal(2')-Pro-Lys)-dVal-dPro-NH2(SEQ ID NO:246); Ac-Nle-c(Asp-Pro-Trp-dNal(2')-Lys)-dVal-dPro-NH2(SEQ ID NO:247); Ac-Nle-c(Asp-Pro-Trp-Arg-dNal(2')-Pro-Lys)-dVal-dPro-NH2(SEQ ID NO:248); Ac-Nle-c(Asp-Pro-Trp-Arg-dNal(2')-Lys)-dVal-dPro-NH2(SEQ ID NO:249); Ac-Nle-c(Lys-Trp-Arg-dNal(2')-Pro-Asp)-dVal-dPro-NH2(SEQ ID NO:250); Ac-Arg-c(Cys-dAla-His-dNal(2')-Arg-Trp-Cys)-NH2(SEQ ID NO:251); Ac-Arg-c(Asp-dAla-His-dNal(2')-Arg-Trp-Lys)-NH2 (SEQ ID NO: 252); Ac-Arg-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 253); and Ac-Arg-c(Asp-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(EQ ID NO:254), where c represents the expression through R 2 and R 5至8 Either of them is cyclized via a lactam bond or a disulfide bond.

41. The method according to claim 1, wherein the sequence of formula (I) is selected from the group consisting of: Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2')-Pro-Lys)-Nle-NH2 (SEQ ID NO: 255); Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2')-Pro-Asp)-Nle-NH2 (SEQ ID NO: 256); Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2')-Pro-Lys)-Nle-Nle-NH2 (SEQ ID NO: 257); Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2')-Pro-Asp)-Nle-Nle-NH2 (SEQ ID NO: 258); Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2')-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 259); and Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2')-Pro-Asp)-dVal-dPro-NH2(SEQ ID NO:260), where c represents the result of passing through R 2 and R 7 Either of them is cyclized via a lactam bond.

42. The method according to claim 1, wherein the sequence of formula (I) is: Ac-dVal-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:261); or Tyr-Val-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:262), where c represents the expression via R 2 and R 7 Cyclation via lactam bonds.

43. The method according to claim 1, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Glu-c(Asp-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 263); Ac-Glu-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 264); and Ac-Glu-c(Asp-Arg-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:265), where c represents the expression via R 2 and R 7 Cyclation via lactam bonds.

44. The method according to claim 1, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-His-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 266); Ac-Nle-c(Asp-His-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 267); Ac-Arg-c(Asp-Pro-His-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:268); Ac-Arg-c(Asp-His-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:269); Ac-Nle-c(Asp-Pro-His-dNal(2')-His-Trp-Orn)-dVal-dPro-NH2(SEQ ID NO:270); Ac-Nle-c(Asp-His-dNal(2')-His-Trp-Orn)-dVal-dPro-NH2(SEQ ID NO:271); Ac-Nle-c(Asp-Pro-His-dNal(2')-His-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO:272); Ac-Nle-c(Asp-His-dNal(2')-His-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO:273); Ac-Arg-c(Asp-Pro-His-dNal(2')-His-Trp-Orn)-dVal-dPro-NH2(SEQ ID NO:274); Ac-Arg-c(Asp-His-dNal(2')-His-Trp-Orn)-dVal-dPro-NH2(SEQ ID NO:275); Ac-Arg-c(Asp-Pro-His-dNal(2')-His-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO:276); Ac-Arg-c(Asp-His-dNal(2')-His-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO:277); Ac-Nle-c(Asp-Pro-His-dNal(2')-His-Trp-Dap)-dVal-dPro-NH2(SEQ ID NO:278); Ac-Nle-c(Asp-His-dNal(2')-His-Trp-Dap)-dVal-dPro-NH2(SEQ ID NO:279); Ac-Arg-c(Asp-Pro-His-dNal(2')-His-Trp-Dap)-dVal-dPro-NH2(SEQ ID NO:280); Ac-Arg-c(Asp-His-dNal(2')-His-Trp-Dap)-dVal-dPro-NH2(SEQ ID NO:281); Where c represents through R 1 or R 2 and R 7 Cyclation via lactam bonds.

45. The method of claim 1, wherein the non-naturally occurring melanocortin analog comprises a sequence selected from the group consisting of: SEQ ID NO: 10, 14, 33 to 39, 82 to 96, 108 to 111, 119 to 124, 128, 182 to 189, 212 to 281, 394 and 399.

46. ​​The method of claim 1, wherein the non-naturally occurring melanocortin analog comprises SEQ ID NO:

3.

47. The method according to any one of claims 1 to 46, wherein the non-naturally occurring melanocortin analogue is present in the composition.

48. The method of claim 47, wherein the composition further comprises a pharmaceutical salt.

49. The method of claim 47, wherein the composition further comprises a pharmaceutical carrier.

50. The method of claim 47, wherein the non-naturally occurring melanocortin analogue is present in the composition at a concentration of 0.1 mg / mL to 500 mg / mL relative to the total volume of the composition.

51. The method of claim 50, wherein the non-naturally occurring melanocortin analog comprises TCMCB07 (SEQ ID NO:3), and wherein the non-naturally occurring melanocortin analog is present in the composition at a concentration of 5 mg / mL to 100 mg / mL relative to the total volume of the composition.

52. The method of claim 51, wherein the non-naturally occurring melanocortin analog is present in the composition at a concentration of about 50 mg / mL relative to the total volume of the composition.

53. The method according to any one of claims 1 to 52, wherein the non-naturally occurring melanocorticoid analogue is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intravenous, intranasal, or oral administration.

54. The method according to any one of claims 47 to 53, wherein the composition comprising the non-naturally occurring melanocorticoid analogue is administered parenterally to the subject.

55. The method according to any one of claims 47 to 54, wherein the composition comprising the non-naturally occurring melanocortin analogue is subcutaneously administered to the subject.

56. The method according to any one of claims 1 to 55, wherein the non-naturally occurring melanocortin analog crosses the blood-brain barrier of the subject.

57. The method according to any one of claims 1 to 56, wherein the therapeutically effective amount of the non-naturally occurring melanocortin analogue is from 0.001 mg / kg to 25 mg / kg, depending on the weight of the subject.

58. The method according to any one of claims 1 to 57, wherein the therapeutically effective amount of the non-naturally occurring melanocortin analogue is from 0.5 mg / kg to 10 mg / kg, depending on the weight of the subject.

59. The method according to any one of claims 1 to 58, wherein the non-naturally occurring melanocorticoid analogue is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg, depending on the weight of the subject.

60. The method according to any one of claims 1 to 59, wherein the non-naturally occurring melanocorticoid analogue is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg, depending on the weight of the subject.

61. The method of claim 59, wherein the non-naturally occurring melanocortin analogue comprises TCMCB07 (SEQ ID NO:3), and the non-naturally occurring melanocortin analogue is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg, depending on the weight of the subject.

62. The method of claim 60, wherein the non-naturally occurring melanocortin analogue comprises TCMCB07 (SEQ ID NO:3), and the non-naturally occurring melanocortin analogue is administered at least once daily in an amount ranging from 0.5 mg / kg to 10 mg / kg, depending on the weight of the subject.

63. The method according to any one of claims 1 to 62, wherein the non-naturally occurring melanocortin analogue is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

64. The method according to any one of claims 1 to 62, wherein the non-naturally occurring melanocortin analogue is administered to the subject for 1, 5, 7, 14, 21, 28, 35, 40, 45, 50, 60, 75, 90, 100, 110 or 120 days.

65. The method of claim 49, wherein the pharmaceutical carrier comprises water.

66. The method according to any one of claims 1 to 65, wherein the kidney disease and / or the liver disease is a fibrotic disease, optionally wherein the fibrotic kidney disease further includes fibrosis of at least a portion of the subject's kidney, and optionally wherein the fibrotic liver disease further includes fibrosis of at least a portion of the subject's liver.

67. The method according to any one of claims 1 to 65, wherein the kidney disease is chronic kidney disease (CKD) and / or kidney failure.

68. The method of claim 67, wherein the subject has undergone dialysis or is undergoing dialysis.

69. The method according to any one of claims 1 to 65, wherein the liver disease is non-alcoholic fatty liver disease (NAFLD).

70. The method of claim 69, wherein NAFLD is non-alcoholic steatohepatitis (NASH).

71. The method according to any one of claims 1 to 70, wherein the subject experiences loss of appetite, decreased appetite, reduced food consumption, and / or weight loss prior to administration of the non-naturally occurring melanocorticoid analogue.

72. The method of claim 71, wherein the loss of appetite, decreased appetite, reduced food consumption, and / or weight loss are caused by the kidney disease and / or the liver disease.

73. The method of claim 71, wherein the loss of appetite, decreased appetite, reduced food consumption, and / or weight loss are caused by cachexia.

74. The method according to any one of claims 1 to 73, wherein the method (i) stimulates the appetite of the subject; (ii) increases the food consumption of the subject; (iii) prevents or alleviates nausea, vomiting and / or anorexia of the subject; (iv) increases or maintains the weight of the subject; (v) prevents or reduces weight loss of the subject; (vi) increases or maintains the muscle mass of the subject; (vii) prevents or reduces muscle mass loss of the subject; (viii) increases or maintains fat mass of the subject; and / or (ix) prevents or reduces fat mass loss of the subject.

75. The method according to any one of claims 1 to 74, wherein the method increases the subject's weight and / or increases the subject's food consumption.

76. The method of claim 74, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's appetite increases by at least 10% to 200%.

77. The method of claim 74, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's appetite increases by at least 25% to 100%.

78. The method according to claim 75 or 76, wherein during the administration of the non-naturally occurring melanocortin analogue, appetite increases for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

79. The method according to claim 76 or 77, wherein during the administration of the non-naturally occurring melanocortin analogue, appetite increases for at least 1, 5, 7, 14, 21, 28, 35, 40, 45, 50, 60, 75, 90, 100, 110, or 120 days.

80. The method according to any one of claims 76 to 79, wherein the increased appetite is maintained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

81. The method according to any one of claims 74 and 89 to 93, wherein the appetite is assessed by a scale for measuring food cravings, hunger and / or satiety levels.

82. The method of claim 34, wherein the appetite is assessed between meals.

83. The method according to any one of claims 74 and 89 to 95, wherein the subject comprises two or more subjects, and wherein the appetite is the average appetite of the two or more subjects.

84. The method of claim 74 or 75, wherein, after administration of the non-naturally occurring melanocortin analogue, the subject's food consumption increases by at least 25% to 2,000%.

85. The method of claim 74 or 75, wherein, after administration of the non-naturally occurring melanocortin analogue, the subject's food consumption increases by at least 50% to 500%.

86. The method according to claim 84 or 85, wherein during the administration of the non-naturally occurring melanocortin analogue, food consumption increases for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

87. The method according to claim 84 or 85, wherein during the administration of the non-naturally occurring melanocortin analogue, food consumption increases for at least 1, 5, 7, 14, 21, 28, 35, 40, 45, 50, 60, 75, 90, 100, 110, or 120 days.

88. The method according to any one of claims 84 to 87, wherein the increased food consumption is sustained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

89. The method according to any one of claims 74 to 75 and 97 to 101, wherein the food consumption is determined by the total calories (kcal) consumed in a day or the mass (grams or kilograms) of food consumed in a day.

90. The method of claim 74, wherein anorexia is determined by food consumption.

91. The method of claim 74 or 75, wherein, after administration of the non-naturally occurring melanocortin analogue, the subject's body weight increases by at least 5% to 200%.

92. The method of claim 74 or 75, wherein the subject's body weight increases by at least 5% to 25% after administration of the non-naturally occurring melanocortin analogue.

93. The method of claim 74 or 75, wherein the subject's body weight increases by at least 20% to 100% after administration of the non-naturally occurring melanocortin analogue.

94. The method according to any one of claims 91 to 93, wherein the increased weight is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

95. The method of claim 74, wherein, after administration of the non-naturally occurring melanocortin analogue, the subject's muscle mass increases by at least 1% to 100%.

96. The method of claim 74, wherein, after administration of the non-naturally occurring melanocortin analogue, the subject's muscle mass increases by at least 5% to 15%.

97. The method of claim 74, wherein, after administration of the non-naturally occurring melanocortin analogue, the subject's muscle mass increases by at least 25% to 50%.

98. The method according to any one of claims 95 to 97, wherein the increased muscle mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year or 5 years after the application of the non-naturally occurring melanocortin analogue is discontinued.

99. The method according to any one of claims 74 and 108 to 111, wherein the muscle mass is cardiac muscle mass, skeletal muscle mass, or both.

100. The method of claim 74, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's fat mass increases by at least 1% to 100%.

101. The method of claim 74, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's fat mass increases by at least 5% to 15%.

102. The method of claim 74, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's fat mass increases by at least 25% to 50%.

103. The method according to any one of claims 100 to 102, wherein the increased fat mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

104. The method according to any one of claims 1 to 73, wherein the method stimulates the appetite of the subject compared to a control subject suffering from the kidney disease or the liver disease, wherein the control subject was not given the non-naturally occurring melanocortin analogue.

105. The method of claim 104, wherein the control subject experiences loss of appetite, decreased appetite, reduced food consumption, and / or weight loss.

106. The method of claim 105, wherein the loss of appetite, decreased appetite, reduced food consumption, and / or weight loss are caused by the kidney disease or the liver disease.

107. The method of claim 105, wherein the loss of appetite, decreased appetite, reduced food consumption, and / or weight loss are caused by cachexia.

108. The method according to any one of claims 104 to 107, wherein the appetite of the subject increases by at least 10% to 200% relative to the appetite of the control subject after the administration.

109. The method according to any one of claims 104 to 107, wherein, relative to the appetite of the control subject, the appetite of the subject increases by at least 25% to 100% after the administration.

110. The method according to claim 108 or 109, wherein during the administration of the non-naturally occurring melanocortin analogue, appetite increases for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

111. The method according to claim 108 or 109, wherein during the administration of the non-naturally occurring melanocortin analogue, appetite increases for at least 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

112. The method according to any one of claims 108 to 111, wherein the increased appetite is maintained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

113. The method according to any one of claims 105 to 112, wherein the appetite is assessed by a scale for measuring food cravings, hunger and / or satiety levels.

114. The method of claim 113, wherein the appetite is assessed between meals.

115. The method according to any one of claims 104 to 114, wherein the subject comprises two or more subjects, and wherein the appetite of the subject is the average appetite of the two or more subjects.

116. The method according to any one of claims 104 to 115, wherein the control subject comprises two or more control subjects, and wherein the appetite of the control subject is the average appetite of the two or more control subjects.

117. The method according to any one of claims 104 to 107, wherein, relative to the food consumption of the control subject, the food consumption of the subject increases by at least 25% to 2,000% after the administration.

118. The method according to any one of claims 104 to 107, wherein, relative to the food consumption of the control subject, the food consumption of the subject increases by at least 50% to 500% after the administration.

119. The method according to claim 117 or 118, wherein during the application period, food consumption increases for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

120. The method according to claim 117 or 118, wherein during the administration of the non-naturally occurring melanocortin analogue, food consumption increases for at least 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

121. The method according to any one of claims 117 to 120, wherein after the application of the non-naturally occurring melanocortin analogue is stopped, the increased food consumption is maintained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years.

122. The method according to any one of claims 117 to 121, wherein the food consumption is determined by the total calories (kcal) consumed in a day or the mass (grams or kilograms) of food consumed in a day.

123. The method according to any one of claims 104 to 107, wherein the subject gains weight after administration of the non-naturally occurring melanocortin analogue, and wherein the weight gain of the subject after administration is at least 5% to 200% greater than the weight gain of the control subject.

124. The method according to any one of claims 104 to 107, wherein the subject gains weight after administration of the non-naturally occurring melanocortin analogue, and wherein the weight gain of the subject after administration is at least 5% to 25% greater than the weight gain of the control subject.

125. The method according to any one of claims 104 to 107, wherein the subject gains weight after administration of the non-naturally occurring melanocortin analogue, and wherein the weight gain of the subject after administration is at least 20% to 100% greater than the weight gain of the control subject.

126. The method according to any one of claims 123 to 125, wherein the increased weight is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

127. The method according to any one of claims 104 to 107, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's muscle mass increases, and wherein the increase in muscle mass of the subject after administration is at least 1% to 100% greater than the increase in muscle mass of the control subject.

128. The method according to any one of claims 104 to 107, wherein the subject's muscle mass increases after administration of the non-naturally occurring melanocortin analogue, and wherein the increase in muscle mass of the subject after administration is at least 5% to 15% greater than the increase in muscle mass of the control subject.

129. The method according to any one of claims 104 to 107, wherein the subject's muscle mass increases after administration of the non-naturally occurring melanocortin analogue, and wherein the increase in muscle mass of the subject after administration is at least 25% to 50% greater than the increase in muscle mass of the control subject.

130. The method according to any one of claims 127 to 129, wherein the increased muscle mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

131. The method according to any one of claims 104 to 107, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's fat mass increases, and wherein the increase in the subject's fat mass after administration is at least 1% to 100% greater than the increase in the fat mass of the control subject.

132. The method according to any one of claims 104 to 107, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's fat mass increases, and wherein the increase in the subject's fat mass after administration is at least 5% to 15% greater than the increase in the fat mass of the control subject.

133. The method according to any one of claims 104 to 107, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's fat mass increases, and wherein the increase in the subject's fat mass after administration is at least 25% to 50% greater than the increase in the fat mass of the control subject.

134. The method according to any one of claims 131 to 133, wherein the increased fat mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

135. The method according to any one of claims 1 to 134, wherein the subject is a human being.

136. The method according to any one of claims 1 to 135, wherein the subject is an animal.

137. The method of claim 135, wherein the subject's body mass index (BMI) is between 18.5 kg / m² and 35 kg / m².

138. The method of claim 135, wherein the subject's BMI is less than 20 kg / m2.

139. The method of claim 135, wherein the subject's BMI is less than 18.5 kg / m2.

140. The method according to any one of claims 1 to 139, further comprising administering an appetite regulator to the subject.

141. The method according to any one of claims 1 to 140, wherein the subject did not experience any adverse events after administration of the non-naturally occurring melanocortin analogue.

142. The method according to any one of claims 1 to 141, wherein the subject did not experience any adverse events attributable to the non-naturally occurring melanocortin analogue after the administration.

143. The method according to any one of claims 76 to 83, wherein the non-naturally occurring melanocortin analogue is administered to the subject after the subject has experienced the increase in appetite.

144. The method according to any one of claims 84 to 90, wherein the non-naturally occurring melanocortin analogue is continued to be administered to the subject after the subject has experienced the increase in food consumption.

145. The method according to any one of claims 91 to 94, wherein the non-naturally occurring melanocortin analogue is continued to be administered to the subject after the subject has experienced the increase in weight.

146. The method according to any one of claims 1 to 74, wherein the subject is cachectic prior to administration of the non-naturally occurring melanocorticoid analogue.

147. The method of claim 146, wherein the subject is cachectic if the subject meets the Fearon weight loss criteria.

148. The method of claim 147, wherein the Fearon weight loss criteria include (1) a weight loss of more than 5% within 6 months prior to the administration, or (2) a weight loss of more than 2%, wherein the subject's BMI is less than 20 kg / m². 2 Or the subject may have sarcopenia.

149. The method according to any one of claims 146 to 148, wherein the subject is no longer cachectic after administration of the non-naturally occurring melanocorticoid analogue.

150. The method according to any one of claims 146 to 149, wherein the subject no longer meets the Fearon weight loss criteria after administration of the non-naturally occurring melanocortin analogue.

151. The method of claim 149, wherein after the subject is no longer cachectic, the non-naturally occurring melanocorticoid analogue is continued to be administered to the subject.

152. The method of claim 150, wherein after the subject no longer meets the Fearon weight loss criteria, the non-naturally occurring melanocortin analogue is continued to be administered to the subject.

153. The method according to any one of claims 1 to 70 or 74, wherein the subject is pretreated with the non-naturally occurring melanocortin analogue before becoming cachexia.

154. The method according to any one of claims 1 to 70, 74 or 153, wherein the subject does not meet the Fearon weight loss criteria.

155. Use of non-naturally occurring melanocortin analogues for stimulating appetite and / or increasing weight in subjects with kidney and / or liver disease. The non-naturally occurring melanocortin analogue contains a sequence according to formula (I). X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I) Wherein: R 1 The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), trans-4-guanidino-proline (transPro(guan)), cis-4-guanidino-proline (cisPro(guan)), acetylated trans-4-guanidino-proline (Ac-transPro(guan)), acetylated cis-4-guanidino-proline (Ac-cisPro(guan)), tyrosine, D-tyrosine, dimethyltyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid; R 2 The group consisting of the following items is absent or selected: proline, histidine, D-hydroxyproline (dHyp). trans-Pro(guan), cis-Pro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, leucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine; R 3 The group consisting of the following is absent or selected: histidine, L-proline, trans-Pro(guan), cis-Pro(guan), D-valine, glutamic acid, tryptophanyl arginine (Trp-Arg), glycine, D-leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzozazepine-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazol-(1,5-a)(1,4)diazepine-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazazepine(4,3-b)indol-3(2H)-one (Aia), octahydroindol-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), and indololin-2-carboxylic acid (Ioc). R 4 Select the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, dBip, glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-iodo-D-phenylalanine (p(I)dPhe), p-fluoro-D-phenylalanine (p(F)dPhe), and p-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R 5 The following groups are not present or are selected: arginine, homoarginine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(I)dPhe; R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-phenylalanine, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1'), Aba, Ata, D-tyrosine, Pen, dPen and D-alanine; R 7 The group consisting of the following is absent or selected: glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2') and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R 8 It may be absent or contain lysine; R 9 To R 20 It does not exist; X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated n-leucine; X 2 It may be absent or contain D-proline; X 3 It does not exist; Y 1 The group consisting of the following is absent or selected: D-valine, D-tert-leucine, L-tert-leucine, ortholeucine, and D-proline; Y 2 The group consisting of the following is absent or selected: D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, ortholeucine, and glycine; Y 3 The group consisting of the following is absent or selected: D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine; Y 4 It is absent or is either D-aspartic acid or aspartic acid; Y 5 To Y 8 It does not exist; The non-natural melanocortin analogue is optionally partially cyclized by selecting from the group consisting of: When R 1 For cysteine ​​and R 7 When it is cysteine, R 1 With R 7 Disulfide bonds between them; When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them; When R 1 or R 2 It is glutamic acid or aspartic acid and R 7 When it is lysine or Dap, R 1 or R 2 With R 7 The side-chain lactam bridges between them; When R 2 For lysine and R 7 When it is glutamic acid or aspartic acid, R 2 With R 7 The side-chain lactam bridges between them; When R 1 or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 or R 2 With R 8 The side-chain lactam bridges between them; The conditions are: When R 2 When it is dAsp, then R 7 Not for dLys; When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7 Not Arg-Trp-Lys; When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified; When R 3 For Aba, Ata, or Aia, R 6 When it is Aia, then R 4 Not dNal(2'), or R 4 For dNal(2') and R 5 Not for Arg; When R 4 When R is p(Cl)dPhe, then 3 Not Pro or His; When R 4 When p(I)dPhe is used, the non-natural melanocortin analogue is obtained through R. 1 With R 7 The side-chain lactam bridged cyclization between them, and R 2 and R 3 At least one of them is Pro; When Y 2 To Y 4 If it does not exist, then Y 1 It is absent or contains ortholeucine; When R 2 For Pro or Y 2 When it is Hyp, then R 3 Not for Pro; When R 3 R 5 or R 6 If it is not present, then the non-naturally occurring melanocortin analogue is obtained through R. 1 With R 7 The cyclization of lactams between them, or X 1 To X 2 It exists and is Ac-dVal-dPro; When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys or Cys-Pro-dNal(2')-Arg-Trp-Cys, then R 1 Not Ac-Nle or Y 1 To Y 2 Not dVal-dPro, dVal-dVal, or dPro-dPro; and When the aforementioned non-naturally occurring melanocortin analogue is administered via R 2 With R 8 When the lactam bridge between them is cyclized, then R 3 Not His or Y 1 Not dVal.

156. The use according to claim 155, wherein, if present, the N-terminus is modified with a functional group selected from the group consisting of: acyl groups, imine groups, amide groups, urea groups, carbamate groups, sulfonamide groups, and alkylamine groups.

157. The use according to claim 156, wherein, if present, the N-terminus is modified with an acyl group.

158. The use according to claim 157, wherein the acyl group is an acetyl group.

159. The use according to claim 157, wherein the acyl group is a formyl group.

160. The use according to claim 156, wherein, if present, the N-terminus is modified with an imine group.

161. The use according to claim 156, wherein, if present, the N-terminus is modified with an amide group.

162. The use according to claim 161, wherein the amide group is a pyroglutamyl (pGlu) group.

163. The use according to claim 161, wherein the amide group is derived from fatty acids.

164. The use according to claim 155, wherein, if present, the N-terminus is not modified.

165. The use according to claim 155, wherein the C-terminus is modified with a functional group selected from the group consisting of amide groups, ester groups, and aldehyde groups.

166. The use according to claim 165, wherein the C-terminus is modified with an amide group.

167. The use according to claim 166, wherein the amide group is a -NH alkylamide group or a -NH arylamide group.

168. The use according to claim 167, wherein the -NH arylamide group is a p-nitroaniline group or 7-amino-4-methylcoumarin.

169. The use according to claim 165, wherein the C-terminus is modified with an ester group.

170. The use according to claim 155, wherein the C-terminus is not modified.

171. The use according to claim 155, wherein R 1 It does not exist, and R 2 It is D-aspartic acid.

172. The use according to claim 171, wherein X 1 X 2 and X 3 It does not exist.

173. The use according to claim 155, wherein R 4 It is D-Nal(2').

174. The use according to claim 155, wherein Y 3 To Y 8 It does not exist.

175. The use according to claim 174, wherein: Y 1 It is D-valine and Y 2 It is D-proline; or Y 1 It is D-proline and Y 2 It is D-valine.

176. The use according to claim 155, wherein Y 3 Existence and Y 4 To Y 8 It does not exist.

177. The use according to claim 176, wherein: Y 1 It is either D-valine or D-proline; Y 2 It is D-valine or D-proline; and / or Y 3 It is either D-valine or D-proline.

178. The use according to claim 176, wherein: Y 1 For D-valine, Y 2 It is D-valine and Y 3 It is D-proline; Y 1 For D-proline, Y 2 It is D-valine and Y 3 It is D-valine; Y 1 For D-valine, Y 2 It is D-proline and Y 3 It is D-valine; or Y 1 For D-proline, Y 2 It is D-valine and Y 3 It is D-proline.

179. The use according to claim 155, wherein Y 3 and Y 4 It exists, and Y 5 To Y 8 It does not exist.

180. The use according to claim 179, wherein: Y 1 It is either D-valine or D-proline; Y 2 It is either D-valine or D-proline; Y 3 It is D-valine or D-proline; and / or Y 4 It is either D-valine or D-proline.

181. The use according to claim 179, wherein: Y 1 For D-valine, Y 2 For D-valine, Y 3 It is D-valine and Y 4 It is D-proline; Y 1 For D-proline, Y 2 For D-valine, Y 3 It is D-valine and Y 4 It is D-valine; Y 1 For D-valine, Y 2 For D-proline, Y 3 It is D-valine and Y 4 It is D-valine; Y 1 For D-valine, Y 2 For D-valine, Y 3 It is D-proline and Y 4 It is D-valine; or Y 1 For D-valine, Y 2 For D-proline, Y 3 It is D-valine and Y 4 It is D-proline.

182. The use according to claim 155, wherein R 1 R 2 and R 7 Existence and R 8 To R 20 It does not exist, and the sequence of equation (I) is passed through R. 2 and R 7 Cyclation via lactam bonds.

183. The use according to claim 155, wherein R 1 R 2 R 7 and R 8 Existence and R 9 To R 20 It does not exist, and the sequence of equation (I) is passed through R. 2 and R 8 Cyclation via lactam bonds.

184. The use according to claim 183, wherein: R 1 It is acetylated leucine; R 2 It is aspartic acid; R 3 Choose the group consisting of the following: proline, hydroxyproline, D-hydroxyproline, phenylalanine, and histidine; R 4 For histidine or dNal(2'); R 5 For dNal(2') or arginine; R 6 Choose the group consisting of the following: arginine, D-tryptophan, and L-tryptophan; R 7 It is tryptophan or proline; R 8 It is lysine; Y 1 Choose the group consisting of: D-valine, D-leucine, and D-isoleucine; and / or Y 2 It is D-proline.

185. The use according to claim 183, wherein the sequence of formula (I) is Ac-Nle- c (Asp-Pro-His-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 10; D5), Where c represents through R 2 and R 8 Cyclation via lactam bonds.

186. The use according to claim 155, wherein the sequence of formula (I) is linear.

187. The use according to claim 186, wherein the sequence of formula (I) is Ac-Nle-Pro-dNal(2')-Arg-Trp-dVal-dPro-NH2 (SEQ ID NO:14).

188. The use according to claim 155, wherein the sequence of formula (I) is selected from the group consisting of: Ac-transPro(guan)-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:33); Ac-cis-Pro(guan)-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 34); dTyr-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 35); Tyr-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 36); Dmt-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 37); Ac-Glu-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 38); and Ac-Asn-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:39), Where c represents through R 2 and R 7 Cyclation via lactam bonds.

189. The use according to claim 155, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-dLeu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:82); Ac-Nle-c(Asp-dIle-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:83); Ac-Nle-c(Asp-dVal-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-c(Asp-Trp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:85); Ac-Nle-c(Asp-dTrp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Nle-c(Asp-transPro(guan)-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:87); Ac-Nle-c(Asp-cis-Pro(guan)-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:88); Ac-Nle-c(Asp-Val-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:89); Ac-Nle-c(Asp-Ile-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:90); Ac-Nle-c(Asp-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:91); Ac-Nle-c(Asp-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:92); Ac-Nle-c(Asp-Arg-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:93); Ac-Nle-c(Asp-dLeu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:94); Ac-Nle-c(Asp-dAla-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:95); and Ac-Nle-c(Asp-dMet-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:96), where c represents the result of passing through R 2 and R 7 Cyclation via lactam bonds.

190. The use according to claim 155, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2')-dHis-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:108); Ac-Nle-c(Asp-Pro-dNal(2')-dAla-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 109); Ac-Nle-c(Asp-Pro-dNal(2')-dAsp-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 110); and Ac-Nle-c(Asp-Pro-dNal(2')-dGlu-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:111), where c represents the expression via R 2 and R 7 Cyclation via lactam bonds.

191. The use according to claim 155, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dNal(1')-Lys)-dVal-dPro-NH2(SEQ ID NO:119); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dPhe-Lys)-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dNal(2')-Lys)-dVal-dPro-NH2 (SEQ ID NO: 121); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dTyr-Lys)-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dHis-Lys)-dVal-dPro-NH2 (SEQ ID NO: 123); and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dAla-Lys)-dVal-dPro-NH2(SEQ ID NO:124), where c represents the expression via R 2 and R 7 Cyclation via lactam bonds.

192. The use according to claim 155, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-OH(SEQ ID NO:128); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dVal-dPro-NH2 (SEQ ID NO: 182); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dPro-NH2 (SEQ ID NO: 183); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dVal-NH2 (SEQ ID NO: 184); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dTle-NH2 (SEQ ID NO: 185); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dTle-dPro-NH2 (SEQ ID NO: 186); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dTle-dTle-dVal-NH2 (SEQ ID NO: 187); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dTle-NH2 (SEQ ID NO: 188); and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dTle-NH2(SEQ ID NO:189), where c represents the result of passing through R 2 and R 7 Cyclation via lactam bonds.

193. The use according to claim 155, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Che-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:212); Ac-Nle-c(Asp-Oic-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 213); Ac-Nle-c(Asp-Ioc-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 214); Ac-Nle-c(Asp-Tic-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 215); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 216); Ac-Nle-c(Asp-His-dNal(2')-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:217); Ac-Nle-c(Asp-His-dNal(2')-trans-Pro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:218); Ac-Nle-c(Asp-His-dNal(2')-cis-Pro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:219); Ac-Nle-c(Asp-Pro-dNal(2')-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:220); Ac-Nle-c(Asp-Pro-dNal(2')-trans-Pro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:221); Ac-Nle-c(Asp-Pro-dNal(2')-cis-Pro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:222); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Aba-Lys)-dVal-dPro-NH2 (SEQ ID NO:223); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Ata-Lys)-dVal-dPro-NH2 (SEQ ID NO:224); Ac-Nle-c(Asp-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:225); Ac-Nle-c(Asp-Glu-dNal(2')-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO:226); Ac-Nle-c(Asp-Pro-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:227); Ac-Nle-c(Asp-Pro-Glu-dNal(2')-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO:228); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO:229); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dPro-dPro-Lys-Asp-NH2 (SEQ IDNO: 230); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dPro-dPro-dLys-dAsp-NH2 (SEQ IDNO: 231); Ac-Glu-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO: 232); and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO: 233), Where c represents through R 2 and R 7 Cyclation via lactam bonds.

194. The use according to claim 155, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Glu-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:234); Ac-Nle-c(Asp-Glu-His-dNal(2')-Arg-Trp-Gly-Lys)-dVal-dPro-NH2(SEQ ID NO:235); Ac-Nle-c(Asp-dAla-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:236); Ac-Arg-c(Asp-dAla-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 237); Ac-Arg-c(Asp-dAla-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 238); Ac-Arg-c(Cys-dAla-His-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 239); Ac-dArg-c(Asp-dAla-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 240); Ac-Arg-c(Asp-dAla-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 241); Ac-dArg-c(Asp-dAla-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 242); Ac-Nle-c(Asp-Ala-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 243); Ac-Arg-c(Asp-Ala-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 244); Ac-dArg-c(Asp-Ala-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 245); Ac-Nle-c(Asp-Trp-Arg-dNal(2')-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 246); Ac-Nle-c(Asp-Pro-Trp-dNal(2')-Lys)-dVal-dPro-NH2 (SEQ ID NO: 247); Ac-Nle-c(Asp-Pro-Trp-Arg-dNal(2')-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 248); Ac-Nle-c(Asp-Pro-Trp-Arg-dNal(2')-Lys)-dVal-dPro-NH2 (SEQ ID NO: 249); Ac-Nle-c(Lys-Trp-Arg-dNal(2')-Pro-Asp)-dVal-dPro-NH2 (SEQ ID NO: 250); Ac-Arg-c(Cys-dAla-His-dNal(2')-Arg-Trp-Cys)-NH2 (SEQ ID NO: 251); Ac-Arg-c(Asp-dAla-His-dNal(2')-Arg-Trp-Lys)-NH2 (SEQ ID NO: 252); Ac-Arg-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 253); and Ac-Arg-c(Asp-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(EQ ID NO:254), where c represents the expression through R 2 and R 5至8 Either of them is cyclized via a lactam bond or a disulfide bond.

195. The use according to claim 155, wherein the sequence of formula (I) is selected from the group consisting of: Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2')-Pro-Lys)-Nle-NH2(SEQ ID NO:255); Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2')-Pro-Asp)-Nle-NH2 (SEQ ID NO: 256); Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2')-Pro-Lys)-Nle-Nle-NH2 (SEQ ID NO: 257); Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2')-Pro-Asp)-Nle-Nle-NH2 (SEQ ID NO: 258); Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2')-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 259); and Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2')-Pro-Asp)-dVal-dPro-NH2(SEQ ID NO:260), where c represents the result of passing through R 2 and R 7 Either of them is cyclized via a lactam bond.

196. The use according to claim 155, wherein the sequence of formula (I) is: Ac-dVal-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:261); or Tyr-Val-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:262), where c represents the expression via R 2 and R 7 Cyclation via lactam bonds.

197. The use according to claim 155, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Glu-c(Asp-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:263); Ac-Glu-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 264); and Ac-Glu-c(Asp-Arg-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 265), Where c represents through R 2 and R 7 Cyclation via lactam bonds.

198. The use according to claim 155, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-His-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 266); Ac-Nle-c(Asp-His-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 267); Ac-Arg-c(Asp-Pro-His-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 268); Ac-Arg-c(Asp-His-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 269); Ac-Nle-c(Asp-Pro-His-dNal(2')-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 270); Ac-Nle-c(Asp-His-dNal(2')-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 271); Ac-Nle-c(Asp-Pro-His-dNal(2')-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 272); Ac-Nle-c(Asp-His-dNal(2')-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 273); Ac-Arg-c(Asp-Pro-His-dNal(2')-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 274); Ac-Arg-c(Asp-His-dNal(2')-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 275); Ac-Arg-c(Asp-Pro-His-dNal(2')-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 276); Ac-Arg-c(Asp-His-dNal(2')-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 277); Ac-Nle-c(Asp-Pro-His-dNal(2')-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 278); Ac-Nle-c(Asp-His-dNal(2')-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 279); Ac-Arg-c(Asp-Pro-His-dNal(2')-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 280); Ac-Arg-c(Asp-His-dNal(2')-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 281); Where c represents through R 1 or R 2 and R 7 Cyclation via lactam bonds.

199. The use according to claim 155, wherein the non-naturally occurring melanocortin analog comprises a sequence selected from the group consisting of: SEQ ID NO: 10, 14, 33 to 39, 82 to 96, 108 to 111, 119 to 124, 128, 182 to 189, 212 to 281, 394 and 399.

200. The use according to claim 155, wherein the non-naturally occurring melanocortin analog comprises SEQ ID NO:

3.

201. The use according to any one of claims 155 to 200, wherein the non-naturally occurring melanocortin analogue is present in the composition.

202. The use according to claim 201, wherein the composition further comprises a pharmaceutical salt.

203. The use according to claim 201, wherein the composition further comprises a pharmaceutical carrier.

204. The use according to claim 201, wherein the non-naturally occurring melanocortin analog is present in the composition at a concentration of 0.1 mg / mL to 500 mg / mL relative to the total volume of the composition.

205. The use according to claim 204, wherein the non-naturally occurring melanocortin analog comprises TCMCB07 (SEQ ID NO:3), and wherein the non-naturally occurring melanocortin analog is present in the composition at a concentration of 5 mg / mL to 100 mg / mL relative to the total volume of the composition.

206. The use according to claim 205, wherein the non-naturally occurring melanocortin analog is present in the composition at a concentration of about 50 mg / mL relative to the total volume of the composition.

207. The use according to any one of claims 155 to 206, wherein the non-naturally occurring melanocorticoid analogue is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intravenous, intranasal, or oral administration.

208. The use according to any one of claims 201 to 207, wherein the composition comprising the non-naturally occurring melanocorticoid analogue is administered parenterally to the subject.

209. The use according to any one of claims 201 to 208, wherein the composition comprising the non-naturally occurring melanocortin analogue is administered subcutaneously to the subject.

210. The use according to any one of claims 155 to 209, wherein the non-naturally occurring melanocortin analog crosses the blood-brain barrier of the subject.

211. The use according to any one of claims 155 to 210, wherein the therapeutically effective amount of the non-naturally occurring melanocortin analogue is from 0.001 mg / kg to 25 mg / kg, depending on the weight of the subject.

212. The use according to any one of claims 155 to 211, wherein the therapeutically effective amount of the non-naturally occurring melanocortin analogue is from 0.5 mg / kg to 10 mg / kg, depending on the weight of the subject.

213. The use according to any one of claims 155 to 212, wherein the non-naturally occurring melanocorticoid analogue is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg, depending on the weight of the subject.

214. The use according to any one of claims 155 to 213, wherein the non-naturally occurring melanocorticoid analogue is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg, depending on the weight of the subject.

215. The use according to claim 213, wherein the non-naturally occurring melanocortin analog comprises TCMCB07 (SEQ ID NO:3), and the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg, depending on the weight of the subject.

216. The use according to claim 214, wherein the non-naturally occurring melanocortin analog comprises TCMCB07 (SEQ ID NO:3), and the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.5 mg / kg to 10 mg / kg, depending on the weight of the subject.

217. The use according to any one of claims 155 to 216, wherein the non-naturally occurring melanocortin analogue is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

218. The use according to any one of claims 155 to 217, wherein the non-naturally occurring melanocortin analogue is administered to the subject for 1, 5, 7, 14, 21, 28, 35, 40, 45, 50, 60, 75, 90, 100, 110 or 120 days.

219. The use according to claim 203, wherein the pharmaceutical carrier comprises water.

220. The use according to any one of claims 155 to 219, wherein the kidney disease and / or the liver disease is a fibrotic disease, optionally wherein the fibrotic kidney disease further includes fibrosis of at least a portion of the subject's kidney, and optionally wherein the fibrotic liver disease further includes fibrosis of at least a portion of the subject's liver.

221. The use according to any one of claims 155 to 219, wherein the kidney disease is chronic kidney disease (CKD) and / or kidney failure.

222. The use according to claim 221, wherein the subject has undergone dialysis or is undergoing dialysis.

223. The use according to any one of claims 155 to 219, wherein the liver disease is non-alcoholic fatty liver disease (NAFLD).

224. The use according to claim 223, wherein NAFLD is non-alcoholic steatohepatitis (NASH).

225. Use according to any one of claims 155 to 224, wherein the subject experienced loss of appetite, decreased appetite, reduced food consumption, and / or weight loss prior to administration of the non-naturally occurring melanocorticoid analogue.

226. The use according to claim 225, wherein the loss of appetite, decreased appetite, reduced food consumption and / or weight loss are caused by the kidney disease and / or the liver disease.

227. The use according to claim 225, wherein the loss of appetite, decreased appetite, reduced food consumption and / or weight loss are caused by cachexia.

228. The use according to any one of claims 155 to 227, wherein the use (i) stimulates the appetite of the subject; (ii) increases the food consumption of the subject; (iii) prevents or alleviates nausea, vomiting and / or anorexia of the subject; (iv) increases or maintains the weight of the subject; (v) prevents or reduces weight loss of the subject; (vi) increases or maintains the muscle mass of the subject; (vii) prevents or reduces muscle mass loss of the subject; (viii) increases or maintains fat mass of the subject; and / or (ix) prevents or reduces fat mass loss of the subject.

229. The use according to any one of claims 155 to 228, wherein the use increases the subject's weight and / or increases the subject's food consumption.

230. The use according to claim 228, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's appetite increases by at least 10% to 200%.

231. The use according to claim 228, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's appetite increases by at least 25% to 100%.

232. The use according to claim 229 or 230, wherein during the application of the non-naturally occurring melanocortin analogue, appetite increases for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

233. The use according to claim 230 or 231, wherein during the administration of the non-naturally occurring melanocortin analogue, appetite increases for at least 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

234. The use according to any one of claims 230 to 233, wherein the increased appetite is sustained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

235. The use according to any one of claims 225 to 232, wherein the appetite is assessed by a scale for measuring food cravings, hunger and / or satiety levels.

236. The use according to claim 235, wherein the appetite is assessed between meals.

237. The use according to any one of claims 225 to 232, wherein the subject comprises two or more subjects, and wherein the appetite is the average appetite of the two or more subjects.

238. The use according to claim 228 or 229, wherein, after administration of the non-naturally occurring melanocortin analogue, the subject's food consumption increases by at least 25% to 2,000%.

239. The use according to claim 228 or 229, wherein, after administration of the non-naturally occurring melanocortin analogue, the subject's food consumption increases by at least 50% to 500%.

240. The use according to claim 238 or 239, wherein during the application of the non-naturally occurring melanocortin analogue, food consumption increases for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

241. The use according to claim 238 or 239, wherein during the application of the non-naturally occurring melanocortin analogue, food consumption increases for at least 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

242. The use according to any one of claims 238 to 241, wherein the increased food consumption is sustained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

243. The use according to any one of claims 238 to 242, wherein the food consumption is determined by the total calories (kcal) consumed in a day or the mass (grams or kilograms) of food consumed in a day.

244. The use according to claim 228, wherein anorexia is determined by food consumption.

245. The use according to claim 228 or 229, wherein the subject's body weight increases by at least 5% to 200% after administration of the non-naturally occurring melanocortin analogue.

246. The use according to claim 228 or 229, wherein the subject's body weight increases by at least 5% to 25% after administration of the non-naturally occurring melanocortin analogue.

247. The use according to claim 228 or 229, wherein the subject's body weight increases by at least 20% to 100% after administration of the non-naturally occurring melanocortin analogue.

248. The use according to any one of claims 245 to 247, wherein the increased weight is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

249. The use according to claim 228, wherein, after administration of the non-naturally occurring melanocortin analogue, the subject's muscle mass increases by at least 1% to 100%.

250. The use according to claim 228, wherein, after administration of the non-naturally occurring melanocortin analogue, the subject's muscle mass increases by at least 5% to 15%.

251. The use according to claim 228, wherein, after administration of the non-naturally occurring melanocortin analogue, the subject's muscle mass increases by at least 25% to 50%.

252. The use according to any one of claims 249 to 251, wherein the increased muscle mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year or 5 years after the application of the non-naturally occurring melanocortin analogue is discontinued.

253. The use according to any one of claims 228 and 262 to 265, wherein the muscle mass is cardiac muscle mass, skeletal muscle mass, or both.

254. The use according to claim 228, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's fat mass increases by at least 1% to 100%.

255. The use according to claim 228, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's fat mass increases by at least 5% to 15%.

256. The use according to claim 228, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's fat mass increases by at least 25% to 50%.

257. The use according to any one of claims 254 to 256, wherein the increased fat mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

258. The use according to any one of claims 155 to 227, wherein the use stimulates the appetite of the subject compared to a control subject suffering from the kidney disease or the liver disease, wherein the control subject was not given the non-naturally occurring melanocortin analogue.

259. The use according to claim 258, wherein the control subject experiences loss of appetite, decreased appetite, reduced food consumption, and / or weight loss.

260. The use according to claim 259, wherein the loss of appetite, decreased appetite, reduced food consumption and / or weight loss are caused by the kidney disease or the liver disease.

261. The use according to claim 259, wherein the loss of appetite, decreased appetite, reduced food consumption and / or weight loss are caused by cachexia.

262. The use according to any one of claims 258 to 261, wherein, relative to the appetite of the control subject, the appetite of the subject increases by at least 10% to 200% after the administration.

263. The use according to any one of claims 258 to 261, wherein, relative to the appetite of the control subject, the appetite of the subject increases by at least 25% to 100% after the administration.

264. The use according to claim 262 or 263, wherein during the application of the non-naturally occurring melanocortin analogue, appetite increases for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

265. The use according to claim 262 or 263, wherein during the administration of the non-naturally occurring melanocortin analogue, appetite increases for at least 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

266. The use according to any one of claims 262 to 265, wherein the increased appetite is sustained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

267. The use according to any one of claims 259 to 266, wherein the appetite is assessed by a scale for measuring food cravings, hunger and / or satiety levels.

268. The use according to claim 267, wherein the appetite is assessed between meals.

269. The use according to any one of claims 258 to 268, wherein the subject comprises two or more subjects, and wherein the appetite of the subject is the average appetite of the two or more subjects.

270. The use according to any one of claims 258 to 269, wherein the control subject comprises two or more control subjects, and wherein the appetite of the control subject is the average appetite of the two or more control subjects.

271. The use according to any one of claims 258 to 261, wherein, relative to the food consumption of the control subject, the food consumption of the subject increases by at least 25% to 2,000% after the administration.

272. The use according to any one of claims 258 to 261, wherein, relative to the food consumption of the control subject, the food consumption of the subject increases by at least 50% to 500% after the administration.

273. The use according to claim 271 or 272, wherein during the period of application, food consumption increases for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year or 5 years.

274. The use according to claim 271 or 272, wherein during the application of the non-naturally occurring melanocortin analogue, food consumption increases for at least 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

275. The use according to any one of claims 271 to 274, wherein the increased food consumption is sustained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

276. The use according to any one of claims 271 to 275, wherein the food consumption is determined by the total calories (kcal) consumed in a day or the mass (grams or kilograms) of food consumed in a day.

277. The use according to any one of claims 258 to 261, wherein the subject gains weight after administration of the non-naturally occurring melanocortin analogue, and wherein the weight gain of the subject after administration is at least 5% to 200% greater than the weight gain of the control subject.

278. The use according to any one of claims 258 to 261, wherein the subject gains weight after administration of the non-naturally occurring melanocortin analogue, and wherein the weight gain of the subject after administration is at least 5% to 25% greater than the weight gain of the control subject.

279. The use according to any one of claims 258 to 261, wherein the subject gains weight after administration of the non-naturally occurring melanocortin analogue, and wherein the weight gain of the subject after administration is at least 20% to 100% greater than the weight gain of the control subject.

280. The use according to any one of claims 277 to 279, wherein the increased weight is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

281. The use according to any one of claims 258 to 261, wherein after administration of the non-naturally occurring melanocortin analogue, the muscle mass of the subject increases, and wherein the increase in muscle mass of the subject after administration is at least 1% to 100% greater than the increase in muscle mass of the control subject.

282. The use according to any one of claims 258 to 261, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's muscle mass increases, and wherein the increase in muscle mass of the subject after administration is at least 5% to 15% greater than the increase in muscle mass of the control subject.

283. The use according to any one of claims 258 to 261, wherein after administration of the non-naturally occurring melanocortin analogue, the muscle mass of the subject increases, and wherein the increase in muscle mass of the subject after administration is at least 25% to 50% greater than the increase in muscle mass of the control subject.

284. The use according to any one of claims 281 to 283, wherein the increased muscle mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

285. The use according to any one of claims 258 to 261, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's fat mass increases, and wherein the increase in the subject's fat mass after administration is at least 1% to 100% greater than the increase in the fat mass of the control subject.

286. The use according to any one of claims 258 to 261, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's fat mass increases, and wherein the increase in the subject's fat mass after administration is at least 5% to 15% greater than the increase in the fat mass of the control subject.

287. The use according to any one of claims 258 to 261, wherein after administration of the non-naturally occurring melanocortin analogue, the subject's fat mass increases, and wherein the increase in the subject's fat mass after administration is at least 25% to 50% greater than the increase in the fat mass of the control subject.

288. The use according to any one of claims 184 to 287, wherein the increased fat mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year or 5 years after the application of the non-naturally occurring melanocorticoid analogue is discontinued.

289. The use according to any one of claims 155 to 288, wherein the subject is a human being.

290. The use according to any one of claims 155 to 288, wherein the subject is an animal.

291. The use according to claim 289, wherein the subject's body mass index (BMI) is between 18.5 kg / m2 and 35 kg / m2.

292. The use according to claim 289, wherein the subject's BMI is less than 20 kg / m2.

293. The use according to claim 289, wherein the subject's BMI is less than 18.5 kg / m2.

294. The use according to any one of claims 155 to 293, further comprising administering an appetite regulator to the subject.

295. The use according to any one of claims 155 to 294, wherein the subject did not experience adverse events after administration of the non-naturally occurring melanocortin analogue.

296. Use according to any one of claims 155 to 295, wherein the subject did not experience any adverse events attributable to the non-naturally occurring melanocortin analogue after the administration.

297. Use according to any one of claims 155 to 294, wherein the non-naturally occurring melanocortin analogue is continued to be administered to the subject after the subject has experienced the increase in food consumption.

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