Orally deliverable non-naturally occurring melanocortin analogs and uses thereof for treating substance use disorders

Abstract

Provided herein are non-naturally occurring melanocortin analogs that selectively bind at least a portion of a melanocortin receptor The melanocortin receptor may be a melanocortin 3 receptor (MC3R) or a melanocortin 4 receptor (MC4R). The non-naturally occurring melanocortin analogs may have a dissociation constant (Kd) value for a melanocortin receptor or one or more amino acids thereof that is less than that of a conventional melanocortin analog.

Description

ORALLY DELIVERABLE NON-NATURALLY OCCURRING MELANOCORTIN ANALOGS AND USES THEREOF FOR TREATING SUBSTANCE USE DISORDERSCROSS-REFERENCE TO RELATED APPLICATION(S)

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 554,944, filed February 16, 2024; U.S. Provisional Patent Application No. 63 / 557,409, filed February 23, 2024; U.S. Provisional Patent Application No. 63 / 572,896, filed April 1 , 2024; U.S. Provisional Patent Application No. 63 / 573,433, filed April 2, 2024; U.S. Provisional Patent Application No. 63 / 632,496, filed April 10, 2024; U.S. Provisional Patent Application No. 63 / 637,285, filed April 22, 2024; U.S. Provisional Patent Application No. 63 / 640,864, filed April 30, 2024; U.S. Provisional Patent Application No. 63 / 647,545, filed May 14, 2024; U.S. Provisional Patent Application No. 63 / 650,368, filed May 21 , 2024; U.S. Provisional Patent Application No. 63 / 654,876, filed May 31 , 2024; U.S. Provisional Patent Application No. 63 / 656,579, field June 5, 2024; U.S. Provisional Patent Application No. 63 / 663,689, filed June 24, 2024; U.S. Provisional Patent Application No. 63 / 675,219, filed July 24, 2024; U.S. Provisional Patent Application No. 63 / 681 ,055, filed August 8, 2024; and of U.S. Provisional Patent Application No. 63 / 692,605, filed September 9, 2024, all of which are incorporated herein by reference in their entirety.INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] This application contains an ST.26 compliant Sequence Listing, which is submitted concurrently in xml format and hereby incorporated by reference in its entirety. The .xml copy, created on February 13, 2025, is titled “146316_8023_W002_SL. xml” and is 1 ,048,420 bytes in size.BACKGROUND

[0003] Melanocortin receptors (e.g., melanocortin 3 receptor, melanocortin 4 receptor) are major molecular targets for pain management. The vast majority of clinically prescribed pain medications are melanocortin receptor ligands (i.e., opioid drugs) that are structurally similar to or derived from morphine or other opiates. While these medications serve as effective painkillers, usage can result in several unwantedadverse side effects, including increased tolerance, addiction, overdose, respiratory distress, and constipation.

[0004] Opioid and other substance addictions, for example, alcohol and nicotine addictions, contribute to millions of premature deaths each year. Although current therapies aimed at treating addiction can be effective, many substance users are unable to overcome their addiction, despite having a desire to quit.

[0005] Even after recent advances in pain medication development, there remains considerable need for new medications to manage pain with improved therapeutic profiles (e.g., robust therapeutic activity and reduced unwanted adverse side effects) compared to conventional opioid drugs. There is also a growing demand for new therapies to treat opioid use disorders (i.e., opioid addictions) and other addictions (e.g., alcohol use disorder, and nicotine addiction).SUMMARY

[0006] The present technology comprises non-naturally occurring melanocortin analogs and associated used. In some embodiments, the present technology comprises non-naturally occurring melanocortin analog comprising a sequence according to Formula (IC):R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IC), wherein:R1is Nle;R2is Asp or Glu;R3is Pro;R4is p(F)dPhe or dPhe;R5is Arg;R6is Trp;R7is Orn;Y1is dVal;Y2is dPro; andthe non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7, provided that: when R4is dPhe, then R2is GluBRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG 1 . illustrates 24-hour plasma concentrations of non-naturally occurring melanocortin analogs of the present technology following oral administration of Compound Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 19; M1 ) to Cynomolgus Monkeys at 30.0 mg / kg.

[0008] FIGS. 2A-2C illustrate 24-hour plasma concentrations of non-naturally occurring melanocortin analogs of the present technology following oral (PO) administration of Compound D (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2; SEQ ID NO: 218; 07) to Cynomolgus Monkeys at 3 mg / kg, 10.0 mg / kg, 30.0 mg / kg, or 60 mg / kg.

[0009] FIGS. 3A-3D illustrate 24-hour plasma and cerebrospinal fluid (CSF) concentrations of non-naturally occurring melanocortin analogs of the present technology following subcutaneous (SC) administration of Compound D (FIGS. 3A-3D) to Rats at 1 .0 mg / kg, 3.0 mg / kg, and 10.0 mg / kg.

[0010] FIGS. 4A-4D illustrate plasma and CSF concentrations of non-naturally occurring melanocortin analogs following IP administration of Compound D to Rats at 1.0 mg / kg, 3.0 mg / kg, and 10.0 mg / kg.

[0011] FIGS. 5A-5C illustrate 24-hour plasma and CSF concentrations of non- naturally occurring melanocortin analogs of the present technology following PO administration of Compound D to Rats at 10.0 mg / kg and 30.0 mg / kg.

[0012] FIGS. 6A-6D show the plasma and CSF concentration of Compound F (Ac- Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 31 ; A3) following SC administration to Rats at 1.0 mg / kg, 3.0 mg / kg, and 10.0 mg / kg.

[0013] FIGS. 7A-7C show the plasma and CSF concentration of Compound F of FIGS. 6A-6D following IP administration to Rats at 1.0 mg / kg, 3.0 mg / kg, and 10.0 mg / kg.

[0014] FIGS. 8 shows the plasma and CSF concentration of Compound F of FIGS. 6A-6D following IV bolus administration to Rats at 1 .0 mg / kg.

[0015] FIG. 9 shows the mean plasma concentration of Compound F of FIGS. 6A- 6D over time following SC, IP, or IV bolus administration in rats at different dosages.

[0016] FIGS. 10A and 10B show preliminary weight loss and daily food intake results in rats administered 3 mg / kg of A3 (Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal- dPro-NH2; SEQ ID NO: 31 ), 07 (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2; SEQ ID NO: 218) and 01 1 (Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 216).

[0017] FIGS. 1 1 A-1 1 D show food intake (g) at baseline in monkeys having diet- induced obesity (n=6) from 0.5 to 72 hours after saline administration at day 1 (D1 ). FIG. 11 A shows net weight of food intake among individual monkeys. FIG. 1 1 B shows net weight of food intake for each group average. FIG. 1 1 C shows cumulative food intake among individual monkeys. FIG. 1 1 D shows cumulative food intake for each group average.

[0018] FIGS. 12A-12H show food intake (g) in the same monkeys as FIGS. 1 1 A- 11 D administered 1 mg / kg or 3 mg / kg of 07 (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]- dVal-dPro-NH2; SEQ ID NO: 218) or 01 1 (Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal- dPro-NH2; SEQ ID NO: 216) on day 8 (D8). FIG. 12A shows net weight of food intake among individual monkeys at day 8 (D8). FIG. 12B shows net weight of food intake for each group average of monkeys administered the same compound at D8. FIG. 12C shows cumulative food intake among individual monkeys of FIG. 12A at D8. FIG. 12D shows cumulative food intake for each group average of monkeys of FIG.12C administered the same compound at D8. FIG. 12E shows net weight of food intake among individual monkeys at day 12 (D12). FIG. 12F shows net weight of food intake for each group average of monkeys administered the same compound at D12. FIG. 12G shows cumulative food intake among individual monkeys at D12. FIG. 12H shows cumulative food intake for each group average of monkeys administered the same compound at D12.

[0019] FIGS. 13A-13D show food intake patterns in the monkeys administered saline of FIGS. 1 1 A-1 1 D, relative compared to the same monkeys administered 1 mg / kg or 3 mg / kg of 07 (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ IDNO: 218) or 011 (Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 216) (FIGS. 13C and 13D) in FIGS. 12A-12H.

[0020] FIGS. 14A-14C show changes in daily caloric intake (FIG. 14A), cumulative caloric intake (FIG. 14B), percent change in caloric consumption from baseline through day 6 (FIG. 14C) for diet-induced obese monkeys orally administered 10 mg / kg of 07 (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 218). (PO: oral administration; QD: once daily).

[0021] FIGS. 15A-15J show changes in cumulative caloric intake, percent change in caloric consumption from baseline, food intake of a normal diet, food intake of a high fat diet, food intake in calories, and food preference for diet-induced obese monkeys orally administered 07 (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 218) or 01 1 (Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 216). (PO: oral administration; QD: once daily; BID: twice daily).

[0022] FIG. 15K shows normalized cumulative food consumption in rats subcutaneously administered MC4R selective agonists (A07D (Ac-Nle-c[Asp-Pro- dPhe-Arg-Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 31 ), 07 (Ac-Nle-c[Glu-Pro-p(F)dPhe- Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 218) and 011 (Ac-Nle-c[Glu-Pro-dPhe-Arg- Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 216)) (n=5 per group) or a same dose of MC3R / MC4R co-agonists (010 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2; SEQ ID NO: 326)) (n=5) compared to saline controls (n=4). Rats were administered 0.5 mg / kg A07D, 07, 010, or 01 1 for days 1 -7 and 1 mg / kg for days 8- 17.

[0023] FIGS. 16A-16G show changes in body weight for diet included obese monkeys orally administered 07 (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2; SEQ ID NO: 218). FIGS. 16A and 16B show daily body weight (FIG. 16A) and percent change in body weight from baseline (FIGS. 16B) for the diet-induced obese monkeys of FIGS. 14A-14C through day 8. FIGS. 16C shows percent change in body weight as a percentage of initial weight for the monkeys of FIGS. 16A and 16B through day 15. FIG. 16D shows body weight change as a percentage of initial weight in diet induced obese monkeys orally administered 07 or 010 at increasing dosages. FIG. 16E shows body weight change in the monkeys of FIG. 16D. FIG. 16F shows body weight changes as a percentage of initial in monkeys orally administered a non-naturallyoccurring melanocortin analog of the present technology (PO) under different dosing regimens. FIG. 16G shows body weight percent change from initial weight in monkeys orally administered 07 at different doses (PO: oral administration; SC: subcutaneous administration; QD: once daily; BID: twice daily; BIW: twice weekly).

[0024] FIG. 16K shows changes in body weight as a percentage of day 1 in rats administered saline, a melanocortin 4 receptor (MC4R) selective agonist (A07D (Ac- Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 31 ), 07 (Ac-Nle-c[Glu- Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 218) and 01 1 (Ac-Nle-c[Glu- Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 216)), or a same dose of melanocortin 3 receptor (MC3R) / MC4R coagonist ((O10)(Ac-Nle-c[Glu-His-p(F)dPhe- Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 326)).

[0025] FIG. 17 shows plasma concentration of 07 after oral (PO) administration to cynomolgus monkeys at 10 mg / kg or 30 mg / kg.

[0026] FIG. 18 shows plasma concentration of C29 (Ac-dLys-c[Asp-Pro-dPhe-Arg- Trp-Lys]-dLys-dVal-dPro-NH2; SEQ ID NO: 160) after oral administration to cynomolgus monkeys at 10 mg / kg or 30 mg / kg.

[0027] FIGS. 19A-19D show blood glucose levels following administration of A07D to Sprague-Dawley rats at 1 mg / kg or 3 mg / kg. OGTT: Oral Glucose Tolerance Test.

[0028] FIGS. 20A-20G show measurements of diastolic blood pressure (DBP), systolic blood pressure (SBP), heart rate, and heart rate corrected QT interval (QTc) in rats administered setmelanotide at 0.5 mg / kg, 1 .0 mg / kg, 3.0 mg / kg, or 6.0 mg / kg, relative to control rats administered saline (FIGS. 20A-20D) and cardiac data for A07D (“A3”; Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 31 ) up to 180 minutes after subcutaneous injection (FIGS. 20E-20G).

[0029] FIGS. 21A-21 D show the plasma and cerebrospinal fluid (CSF) concentration of A07D (“A3”; Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-l_ys]-dVal-dPro-NH2; SEQ ID NO: 31 ) in rats over time following subcutaneous administration.

[0030] FIG. 22 shows plasma concentration of A07D (Ac-Nle-c[Asp-Pro-dPhe- Arg-Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 31 ) administered at 1 mg / kg intravenously, 10 mg / kg orally, or 30 mg / kg orally to fasted male cynomolgus monkeys.

[0031] FIGS. 23A and 23B show results of a morphine conditioned placed preference (CPP) study in rats administered vehicle and saline, vehicle and morphine, or A07D (Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 31 ) and morphine. FIG 23A illustrates the experimental timeline. FIG 23B illustrates CPP scores in each group before and after each test.DETAILED DESCRIPTION

[0032] The present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating one or more symptoms or conditions associated with pain, addiction, addictive agent use, or withdrawal from an addictive substance using a non-naturally occurring melanocortin analog. In some embodiments, the non- naturally occurring melanocortin analog is administered orally. In some embodiments, the non-naturally occurring melanocortin analog is a melanocortin receptor agonist and / or an melanocortin receptor agonist. In some embodiments, the method comprises preventing, stabilizing, or reducing one or more of a dose used or consumed of an addictive substance, a dependency on an addictive substance, an amount / frequency of an addictive substance, use (e.g., dose or dosage) of an opioid reversal agent, relapse associated with use of an addictive substance, use (e.g., frequency / amount) of a conventional medication used to treat an addiction, an incidence of or need for hospitalization associated with use of an addictive substance, or an incidence in or a need for rehabilitation from an addiction. In some embodiments, the methods promote or increase cessation of an addictive substance.

[0033] The following description is merely exemplary in nature and is not intended to limit the present technology, its applications, or its uses. It should be understood that throughout the drawings, corresponding reference numerals indicate like or corresponding parts and features. The description of specific examples indicated in various embodiments of the present technology are intended for purposes of illustration only and are not intended to limit the scope of the present technology disclosed herein. Moreover, recitation of multiple embodiments having stated features is not intended to exclude other embodiments having additional features or other embodiments incorporating different combinations of the stated features.

[0034] The following description is merely exemplary in nature and is not intended to limit the present technology, its applications, or its uses. It should be understood thatthroughout the drawings, corresponding reference numerals indicate like or corresponding parts and features. The description of specific examples indicated in various embodiments of the present technology are intended for purposes of illustration only and are not intended to limit the scope of the present technology disclosed herein. Moreover, recitation of multiple embodiments having stated features is not intended to exclude other embodiments having additional features or other embodiments incorporating different combinations of the stated features.

[0035] While the embodiments are described in sufficient detail to enable those skilled in the art to practice the present technology, it should be understood that other embodiments may be realized, and that logical changes may be made without departing from the spirit and scope of the present technology. Thus, the detailed description herein is presented for purposes of illustration only and not of limitation. For example, steps recited in any method or process, may be executed in any order and are not limited to the order presented. Moreover, any of the steps thereof may be outsourced to or performed by one or more third parties.Definitions

[0036] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present technology belongs. For the purposes of the present technology, the following terms are defined below.

[0037] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Likewise, any reference to singular includes plural embodiments, and any reference to more than one component may include a singular embodiment.

[0038] The term “about” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by acceptable levels in the art. Typically, such variation may be as much 10% above and below a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length and such variation may be influenced by standard applicable measurement practices. When the term “about” is used in conjunction with a numerical range, itmodifies that range by extending the boundaries above and below the numerical values set forth.

[0039] The terms “administering” or “administer” include delivery of therapies (e.g., non-naturally occurring melanocortin analogs (also referred to herein as peptides)) of the present technology to a subject either by local or systemic administration.

[0040] The terms “active ingredient” and “active compound” refer to a biologically active substance, whether naturally or non-naturally occurring, that is the main component of the pharmaceutical composition which elicits the intended effect of an administered therapeutic. This may be any component that drives the pharmacological activity or direct effect in the diagnosis, cure, mitigation, treatment, or prevention of the conditions associated with the present technology, such as but not limited to, substance use disorders.

[0041] As used herein, a “composition” or a “pharmaceutical composition” refers to a mixture of the active ingredient with other chemical components, such as pharmaceutically acceptable carriers and / or excipients.

[0042] As used herein, a “pharmaceutically acceptable carrier” of the pharmaceutical composition refers to a carrier or diluent that does not cause significant irritation to an organism, does not abrogate the biological activity and properties of the administered active ingredient, and / or does not interact in a deleterious manner with the other components of the composition in which it is contained. The term “carrier” encompasses any excipient, binder, diluent, filler, salt, buffer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. The choice of a carrier for use in a composition will depend upon the intended route of administration for the composition. The preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21 st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005, which is incorporated herein by reference in its entirety). Some examples of physiologically acceptable carriers include antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and othercarbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN® (ICI, Inc.; Bridgewater, N.J.), polyethylene glycol (PEG), and PLURONICS™ (BASF; Florham Park, N.J.). An “excipient” of the first or the pharmaceutical composition refers to an inert substance added to a composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0043] The terms “treat”, “treatment”, and “treating” may also refer to the reduction or inhibition of the progression and / or duration of a disease, the reduction or amelioration of the severity of the disease, and / or the amelioration of one or more symptoms thereof resulting from the administration of one or more therapies.

[0044] As used herein, the terms “effective amount” or “therapeutically effective amount,” refer to that amount of the active ingredient being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated.

[0045] The term “after administration” refers to any duration of time after the non- naturally occurring melanocortin analog or pharmaceutical composition thereof has been administered to a subject. Likewise, the term “prior to” refers to any duration of time before the non-naturally occurring melanocortin analog or pharmaceutical composition thereof has been administered to a subject. Unless otherwise specified, durations of time encompassed by “after administration” or “prior to administration” may include seconds, minutes, hours, days, weeks, months, and years.

[0046] The terms “subject” and “patient” refer to anyone being evaluated for disease, disorder, or condition or being administered a therapeutic or pharmaceutical composition. This includes people without diagnosed or confirmed disease or condition. This also includes people with diagnosed or confirmed disease or condition, such as an alcohol use disorder or an opioid use disorder.

[0047] The term “control subject,” as used herein, refers to any subject used as a basis for comparison to the subject (e.g., test subject). A control subject includes, but is not limited to, any subject who has not been administered the therapeutic orpharmaceutical composition (e.g., the non-naturally occurring melanocortin analog, a therapeutically effective amount of the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof) or administered a placebo.

[0048] “Melanocortin analogs,” “non-naturally occurring melanocortin analogs,” “melanocortin peptides,” “melanocortin receptor peptides,” or “melanocortins,” are used interchangeably and refer to melanocortin-receptor ligands, which are macromolecules containing at least one melanocortin pharmacophore. Melanocortin analogs are typically peptides that bind melanocortin receptors under physiological conditions. Melanocortin analogs include naturally occurring non-naturally occurring melanocortin analogs (i.e., “synthetic peptides” or “synthetic analogs”) and truncated and / or modified versions of melanocortin full-length protein or peptides. For example, the full-length proopiomelanocortin protein (POMC), prior to proteolytic cleavage of “sub-peptides,” consists of 241 amino acids. Tissue-specific proteolytic cleavage of POMC yields peptides ranging in size from 13 amino acids to 76 amino acids. See Bicknell and Lawry, Encyclopedia of Stress, vol. 3, 257-265, Academic Press (2000). Synthesized, non- naturally occurring melanocortin analogs having increased melanocortin receptor activity as discussed herein are approximately 7-12 amino acids in size. Melanocortin analogs exhibit binding functionality with melanocortin receptors. In addition to peptides, the non-naturally occurring melanocortin analogs include small molecule analogs of melanocortin or portions thereof comprised of organic compounds, inorganic compounds, or combinations of peptide and small molecule — i.e., peptide mimetics, or various combinations thereof. “Non-naturally occurring melanocortin analogs” may be structurally similar and / or functionally similar to biological melanocortin proteins in their ability to bind melanocortin receptors. Further, the melanocortin analogs generally contain the pharmacophore: His-Phe-Arg-Trp (SEQ ID NO: 1 ) or a modified version thereof, or a structural or functional peptide mimetic thereof.

[0049] A “pharmacophore” is the minimum set of amino acid residues necessary to achieve a physiological effect; or a small molecule that is (with respect to a receptor) a structural mimic of the amino acid residues required for binding to and activation of a receptor. His-Phe-Arg-Trp (SEQ ID NO: 1 ) and their analogs are the pharmacophore of melanocortin for the regulated physiological effect. Therefore, non-naturally occurring melanocortin pharmacophore analogs may be small peptides or organic moleculesdesigned to mimic the appearance or function (including activation or deactivation of receptor activity) of the melanocortin pharmacophore core sequence peptide.

[0050] A melanocortin receptor “agonist” is a naturally occurring substance or manufactured drug substance or composition that may interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor.

[0051] A melanocortin receptor “antagonist” is a naturally occurring substance or manufactured drug substance or composition that opposes the melanocortin receptor- associated responses normally induced by a melanocortin receptor agonist agent.

[0052] “Potentiated therapeutic activity” refers to an increase in melanocortin activity in a non-naturally occurring melanocortin analog that has undergone derivatization at the N- and / or C-terminus. Such derivatizations do not necessarily involve the pharmacophore, but do imply a relative increase in in vivo biological halflife.

[0053] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating and the like.

[0054] The “peptides” of the present technology may be (a) naturally-occurring, (b) produced by chemical synthesis, (c) produced by recombinant DNA technology, (d) produced by biochemical or enzymatic fragmentation of larger molecules, (e) produced by methods resulting from a combination of methods (a) through (d) listed above, or (f) produced by any other means for producing peptides.

[0055] The term “peptide” as used herein includes any structure comprised of two or more amino acids, including chemical modifications and derivatives of amino acids. The amino acids forming all or a part of a peptide may be naturally occurring amino acids, stereoisomers and modifications of such amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically modified amino acids, constructs or structures designed to mimic amino acids, and the like, so that the term “peptide” includes pseudopeptides and peptidomimetics, including structures which have a non-peptidic backbone. The term “peptide” also includes dimers or multimers of peptides. A “manufactured” peptide includes a peptide produced by chemical synthesis,recombinant DNA technology, biochemical, or enzymatic fragmentation of larger molecules, combinations of the foregoing or, in general, made by any other method. The term “peptide” includes peptides containing a variable number of amino acid residues, optionally with non-amino acid residue groups at the N- and C-termini, such groups including acyl, acetyl, alkenyl, alkyl, N-alkyl, amine, or amide groups, among others.

[0056] By employing chemical synthesis, a useful means of production, it is possible to introduce various amino acids which do not naturally occur along the chain, modify the N- or C-terminus, and the like, thereby providing for improved stability and formulation, resistance to protease degradation, and the like.

[0057] “Amino acids” are molecules containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen and have the generic formula H2N — CHR — COOH, wherein R represents a side chain group. The various a-amino acids differ in the side-chain moiety that is attached to the a-carbon. The “amino acids” of the present technology include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviation. See generally Synthetic Peptides: A User’s Guide, G. A. Grant, editor, W.H. Freeman & Co., New York (1992), the teachings of which are incorporated herein by reference, including the text and table set forth at pages 11 through 24. As set forth above, the term “amino acid” also includes stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. Modified and unusual amino acids are described generally in Synthetic Peptides: A User’s Guide, supra; Hruby et al., Biochem. J. 268:249-262 (1990); and Toniolo, Int. J. Peptide Protein Res. 35:287-300 (1990); the teachings of all of which are incorporated herein by reference.

[0058] The phrase “amino acid side chain moiety” used herein, including as used in the specification and claims, includes any side chain of any amino acid, as the term “amino acid” is defined herein. This thus includes the side chain moiety present in naturally occurring amino acids. It further includes side chain moieties in modifiednaturally occurring amino acids, such as glycosylated amino acids. It further includes side chain moieties in stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids, and the like. For example, the side chain moiety of any amino acid of the present technology is included within the definition. A “derivative” of an amino acid side chain moiety is included within the definition of an amino acid side chain moiety.

[0059] The “derivative” of an amino acid side chain moiety includes any modification to or variation in any amino acid side chain moieties, including a modification 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 noncyclic, substituted or unsubstituted, saturated or unsaturated, alkyl, aryl or aralkyl moieties.

[0060] In the peptides of the present technology, conventional amino acid residues have their conventional meaning as given in Chapter 2400, of the Manual of Patent Examining Procedure, 8thEd. Thus, “Ala” is alanine; “Arg” is arginine; “Asn” is asparagine; “Asp” is aspartic acid; “Cys” is cysteine; “Gin” is glutamine; “Glu” is glutamic acid; “His” is histidine; “He” 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 tryosine; and “Vai” is valine. Unless otherwise indicated, all amino acids abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof may be used. Thus, for example, “L-Phe” is L-phenylalanine; “D- Phe” is D-phenylalanine; “D- / L-Phe” is D-phenylalanine, L-phenylalanine, or combinations thereof; “Phe” is also D-phenylalanine, L-phenylalanine, or combinations thereof, and so on.

[0061] An alpha (a)-amino acid has the generic formula H2N — CaHR — COOH, where R is a side chain moiety and the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (i.e., the a-carbon). Other types of amino acids exist when the amino group is attached to a different carbon atom. For example, beta (P)-amino acids, the carbon atom to which the amino group is attached is separated from the carboxylate group by one carbon atom, Cp.

[0062] When p-amino acids are incorporated into peptides, two main types of - peptides exist: those with the side chain residue, R, on the carbon next to the amine are called p3peptides and those with the side chain residue on the carbon next to the carbonyl group are called p2amino acids.

[0063] Gamma (y)-amino acids are amino acids where the carbon atom to which the amino group attaches is separated from the carboxylate moiety by two carbon atoms.

[0064] For additional modified and unusual amino acids, see §2422 of the MPEP, particularly Table 4 at 2400-24. Additionally, “Ac” indicates N-acetyl and “cyclo” refers to a cyclic structure, which is also shown as “c.” “NH2” indicates an amine group, typically added on the C-terminus of a polypeptide. Accordingly, as used herein, an — NH2 moiety on the C-terminus of a peptide indicates an amide, i.e., — CO — NH2.

[0065] Additional abbreviations are used as herein follows: Nle is norleucine, Nal(2’) is 2'-naphthylalanine, Nal(1 ') is 1 '-naphthylalanine, Tie is tert-leucine, Orn is ornithine, Bip is biphenylalanine; czsPro(guan) is c / s-4-guanidyl-proline, fransPro(guan) is trans-4-guanidyl-proline, Hyp is hydroxyproline; Pen is penicillamine; Tic is 1 ,2,3,4- tetrahydroisoquinoline-3-carboxylic Acid; Aba is 4-amino-1 ,2,4,5-tetra-hydro-2- benzazepin-3-one; Oic is octohydroindole-2-carboxylic acid; Ate is 2-aminotetraline-2- carboxylic acid, APC is 1 -amino-4-phenylcyclohexane-carboxylic acid, APPC is 4- aminophenylpiperidine-4-carboxylic acid, Ata is 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo- [1 ,5-a][1 ,4]diazepin-6(5H)-one, Aia is 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol- 3(2H)-one, Che is 1 -amino-1 -cyclohexanecarboxylic acid, loc is indoline-2-carboxylic acid, Cpe is 1 -amino-1 -cyclopentane carboxylic, and p(CI)dPhe is para-chloro- phenylalanine (F - fluoro, Br - bromo).

[0066] The term “acyl” includes a group RCO — , where R is an organic group. An example is the acetyl group CH3CO — , referred to herein as “Ac.”

[0067] A peptide or aliphatic moiety is “acylated” when an alkyl or substituted alkyl group as defined above is bonded through one or more carbonyl { — (C=O) — } groups. A peptide is most usually acylated at the N-terminus.

[0068] An “amine” includes compounds that contain an amine group ( — NH2).

[0069] An “amide” includes compounds that have a trivalent nitrogen attached to a carbonyl group (i.e., — CO — NH2), such as for example methylamide, ethylamide, propylamide, and the like. A peptide is most usually amidated at the C-terminus by the addition of an amine ( — NH2) moiety to the C-terminal carboxyl group.

[0070] Amino acids, including stereoisomers and modifications of naturally occurring amino acids, protein amino acids, non-protein amino acids, post- translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids (peptide mimetics), and the like, including all of the foregoing, are sometimes referred to herein as “residues.”

[0071] “Substantial degradation” refers to the degradation of the N-terminal extension, the C-terminal extension, both N- and C-terminal degradation or degradation to other regions of the non-naturally occurring melanocortin analog by physiological enzymes and other factors, in such a manner or to a degree that side effects appear. According to one embodiment, a non-naturally occurring melanocortin analog having a C-terminal extension that resists substantial degradation is one where no more than 50% of the administered peptide causes side effects and / or displays a low half-life. In some embodiments, no more than 25% of the administered peptide causes side effects and / or displays a low half-life. More preferably, in some embodiments, less than 10% of the administered peptide causes side effects and / or displays a low half-life, as compared to a non-naturally occurring melanocortin analog that lacks a C-terminal extension.

[0072] The disclosure of all publications, patents, and published patent applications listed herein are hereby incorporated by reference in their entireties, including but not limited to U.S. Patent Nos. 8,541 ,545 and 9,534,018.Non-naturally Occurring Melanocortin Analogs

[0073] The non-naturally occurring melanocortin analogs of the present technology may comprise a non-naturally occurring melanocortin analog or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Non-naturally occurring melanocortin analogs of the present technology may be selective for the melanocortin 4 receptor (MC4R) and / or melanocortin 3 receptor (MC3R) over other melanocortin receptors, i.e., the melanocortin 1 receptor (MC1 R), the melanocortin 2receptor (MC2R), and the melanocortin 5 receptor (MC5R). Some of the non-naturally occurring melanocortin analogs may bind only the MC3R or the MC4R. Alternatively, some of the non-naturally occurring melanocortin analogs may bind the MC3R with greater affinity than the MC4R, whereas other melanocortin analogs may bind the MC4R with greater affinity than the MC3R. Certain melanocortin analogs may bind the MC3R with the same or generally similar affinity as the MC4R.

[0074] The non-naturally occurring melanocortin analogs of the present technology may be full agonists or full antagonists for one or more melanocortin receptors. A full agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect (Emax) agonist value of greater than or equal to 85%. Similarly, a full antagonist may comprise a non-naturally occurring melanocortin analog having an Emax antagonist value of greater than or equal to 85%.

[0075] The non-naturally occurring melanocortin analogs of the present technology may be partial agonists or partial antagonists. A partial agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect Emax agonist value of less than 85%. Similarly, a partial antagonist may comprise a non- naturally occurring melanocortin analog having an Emax antagonist value of less than 85%.

[0076] If a non-naturally occurring melanocortin analog 'S Emax agonist value is greater than it S Emax antagonist value, then the non-naturally occurring melanocortin analog may be classified as an agonist (e.g., a full agonist or a partial agonist).

[0077] If a non-naturally occurring melanocortin analog’s Emax antagonist value is greater than it S Emax agonist value, then the non-naturally occurring melanocortin analog may be classified as an antagonist (e.g., a full antagonist or a partial antagonist).

[0078] The non-naturally occurring melanocortin analogs of the present technology may be one or more of (i) a full MC4R agonist and a full MC3R antagonist; (ii) a full MC4R agonist and a partial MC3R antagonist; and (iii) a full MC4R agonist having no MC3R activity.

[0079] The non-naturally occurring melanocortin analogs of the present technology may avoid cardiac activation typically seen in conventional melanocortin peptide and small molecule agonists. For example, a subject may maintain a stableheart rate, systolic blood pressure, and / or diastolic blood pressure following administration of a melanocortin analog of the present technology.

[0080] The non-naturally occurring melanocortin analogs in accordance with the present technology may have certain structural features that impart specific properties on the analogs, such as, for example, degradation resistance, enhanced epithelial, gastrointestinal, and / or blood brain barrier transport, and binding affinity for the melanocortin 4 receptor and / or melanocortin 3 receptor. Accordingly, in some embodiments, the non-naturally occurring melanocortin analogs have one or more beta hairpin (P-hairpin) and / or beta turn (P-turn) structures. The presence of amino acids that are structurally rigid, such as, for example, Aia, Aba, Ata, Hyp, dHyp, Pro, dPro, fransPro(guan), and c / sPro(guan), may lead to formation of p-hairpin and / or p-turn structures in the non-naturally occurring melanocortin analog. Additionally, disulfide bridges (e.g., cyclization via disulfide bond) may induce and / or stabilize beta-turn structures of the non-naturally occurring melanocortin analogs. In general, cyclization may stabilize beta-turns, and D-amino acids may induce and / or stabilize beta-turns. Further, in some embodiments, melanocortin analogs include D-valine-D-proline (dVal- dPro) chain as their C-terminus, which may provide enhanced transport and resistance to degradation.

[0081] The presence of certain structural features may impart the non-naturally occurring melanocortin analogs of the present technology with specific binding properties. For example, inclusion of p(F)dPhe or dPhe at the R4position may result in enhanced binding and activation of the melanocortin 4 receptor. Accordingly, melanocortin analogs having p(F)dPhe or dPhe at R4may be full agonists on MC4R. Further, inclusion of Pro at the R3position may result in partial agonism of the melanocortin 3 receptor, whereas inclusion of His at the R3position may result in full agonism of the melanocortin 3 receptor.

[0082] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I):X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4-Y5-Y6-Y7(I), wherein:X1is absent or selected from the group consisting of norleucine (Nle), arginine (Arg), D-arginine (dArg), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);X2is absent, phenylalanine (Phe), or Nle;X3is absent, Phe, or Nle;R1is selected from the group consisting of Nle, D-norleucine (dNIe), Ala, D- alanine (dAla), Arg, dArg, Lys, dLys, His, dHis, ornithine (Orn), D-ornithine (dOrn), D- leucine (dLeu), D-tyrosine (dTyr), Phe, D-phenylalanine (dPhe), tryptophan (Trp), D- tryptophan (dTrp), aspartic acid (Asp), cysteine (Cys), and D-cysteine (dCys);R2is selected from the group consisting of Asp, proline (Pro), D-aspartic acid (dAsp), Cys, dCys, D-penicillamine (dPen), Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, glutamic acid (Glu), and dTyr;R3is absent or selected from the group consisting of His, Ala, Pro, hydroxyproline (Hyp), leucine (Leu), D-glutamine (dGIn), Phe, dPhe, Trp, dTrp, Tyr, dTyr, 4-amino- 1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2 ,3]triazolo- [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), 2-aminotetraline-2-carboxylic acid (Ate), 1 -amino-4- phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), tetrahydro-isoquinoline-3-carboxylic acid (Tic), biphenylalanine (Bip), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), indoline-2-carboxylic acid (loc), and 1 -amino-1 -cyclopentane carboxylic (Cpe);R4is selected from the group consisting of Phe, dPhe, para-chloro-D- phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-fluoro- D-phenylalanine (p(F)dPhe);R5is selected from the group consisting of Arg, His, c / s-4-guanidyl-proline (c / sPra(guan)), and trans-4-guanidyl-proline (fransPro(guan));R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, 2’-D- naphthylalanine (dNal(2’)), 2’-naphthylalanine (Nal(2’)), and T-naphthylalanine (Nal(1 ’));R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, penicillamine (Pen), dPen, and Orn;R8is absent or Lys;Y1is absent or selected from the group consisting of valine (Vai), D-valine (dVal), p2-valine (P2-Val), p3-valine (P3-Val), Pro, D-proline (dPro), p-proline (P-Pro), Hyp, D-hydroxyproline (dHyp), dLeu, D-tert-leucine (dTle), Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, asparagine (Asn), D-asparagine (dAsn), and D-threonine (dThr);Y2is absent or selected from the group consisting of Vai, dVal, p2-Val, P3-Val, Pro, dPro, dTle, p-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn;Y3is absent or selected from the group consisting of Vai, dVal, Pro, dPro, dThr, and dLys;Y4is absent or selected from the group consisting of dVal, dPro, and dAsp;Y5is absent or dVal;Y6is absent or dVal;Y7is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1and R7are each independently Cys or dCys; a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn, provided that: when R4is p(Br)dPhe, then R2is dCys; when R4is p(CI)dPhe, then (i) R3is selected from Ata, Aia, and Aba; or (ii) R3is His, R5is Arg; R6is Trp; R7is Lys or dCys, and R1is not Ala, wherein when X1is present, then Y1is dTle and when X1is absent and Y1-Y2is dVal-dPro or dTle-dPro, then eitherR1is not Nle or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2and R7; when R4is p(F)dPhe, then (i) R3is selected from Pro, dGIn, and dTyr, R6is Trp, and R2is not Cys; or (ii) R3is His and R6is Nal(2’) or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2and R7; when R4is dPhe and R1is Asp, then either (i) R2is selected from Trp, Phe, His, Tyr, dPhe, dHis, and dTyr, R3is selected from Pro, Ala, and Leu, R5is Arg, and R6is selected from Trp, Nal( 1 ’), dNal(2’), and Nal(2’); or (ii) R2is selected from Ala, dAla, and Phe, and R3is His, wherein when R2is dAla, then Y1-Y7are absent and when R2is Ala, then R1is not Nle; when R4is dPhe, and R2is Asp, Glu, or dPen, then R3is not His or absent; and when R4is dPhe, R2is Asp, and R3is Pro, then R5is not dNal(2’) or Nal(2’) and Y3-Y7are absent if any of X1-X3are present.

[0083] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein:X1is absent or selected from the group consisting of norleucine (Nle), arginine (Arg), D- arginine (dArg), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D- histidine (dHis);X2is absent, phenylalanine (Phe), or Nle;X3is absent, Phe, or Nle;R1is selected from the group consisting of Nle, D-norleucine (dNIe), Ala, D- alanine (dAla), Arg, dArg, Lys, dLys, His, dHis, ornithine (Orn), D-ornithine (dOrn), D- leucine (dLeu), D-tyrosine (dTyr), Phe, D-phenylalanine (dPhe), tryptophan (Trp), D- tryptophan (dTrp), aspartic acid (Asp), cysteine (Cys), and D-cysteine (dCys);R2is selected from the group consisting of Asp, proline (Pro), D-aspartic acid (dAsp), Cys, dCys, D-penicillamine (dPen), Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, glutamic acid (Glu), and dTyr;R3is absent or selected from the group consisting of His, Ala, Pro, hydroxyproline (Hyp), leucine (Leu), D-glutamine (dGIn), Phe, dPhe, Trp, dTrp, Tyr, dTyr, 4-amino- 1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[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), 2-aminotetraline-2-carboxylic acid (Ate), 1-amino-4- phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), tetrahydro-isoquinoline-3-carboxylic acid (Tic), biphenylalanine (Bip), octohydroindole-2-carboxylic acid (Oic), 1-amino-1 -cyclohexanecarboxylic acid (Che), indoline-2-carboxylic acid (loc), and 1 -amino-1 -cyclopentane carboxylic (Cpe);R4is selected from the group consisting of Phe, dPhe, para-chloro-D- phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-fluoro- D-phenylalanine (p(F)dPhe);R5is selected from the group consisting of Arg, His, c / s-4-guanidyl-proline (c / sPra(guan)), and trans-4-guanidyl-proline (fransPro(guan));R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, 2’-D- naphthylalanine (dNal(2’)), 2’-naphthylalanine (Nal(2’)), and 1 ’-naphthylalanine (Nal(1 ’));R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, penicillamine (Pen), dPen, and Orn;R8is absent or Lys;Y1is absent or selected from the group consisting of valine (Vai), D-valine (dVal), p2-valine (P2-Val), p3-valine (P3-Val), Pro, D-proline (dPro), p-proline (P-Pro), Hyp, D-hydroxyproline (dHyp), dLeu, D-tert-leucine (dTle), Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, asparagine (Asn), D-asparagine (dAsn), and D-threonine (dThr);Y2is absent or selected from the group consisting of Vai, dVal, p2-Val, P3-Val, Pro, dPro, dTle, p-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn;Y3is absent or selected from the group consisting of Vai, dVal, Pro, dPro, dThr, and dLys;Y4is absent or selected from the group consisting of dVal, dPro, and dAsp;Y5is absent or dVal;Y6is absent or dVal;Y7is absent or dPro; andthe non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1and R7are each independently Cys or dCys; a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:Ac-Nle-c[Cys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 232);Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 233);Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 234);Ac-Nle-c[Asp-His-p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 235);Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 236);Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 237);Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2(SEQ ID NO: 238);Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 239);Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 240);Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 241 );Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 242);Ac-Nle-c[Asp-dPhe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 243);Ac-Nle-c[Asp-dGln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 244);Ac-Nle-c[Asp-Trp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 245);Ac-Nle-c[Asp-dTrp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 246);Ac-Nle-c[Asp-Tyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 247);Ac-Nle-c[Asp-dTyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 248);Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 249);Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 250);Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 251 );Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 252);Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 253);Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 254);Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 255);Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 256);Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 257);Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 258);Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 259);Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 260);Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 261 );Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 262);Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 263);Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 264);Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 265);Ac-Nle-c[Glu-His-p(Br)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 266);Ac-Nle-c[Asp-Bip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 267);Ac-Nle-c[Asp-dHis-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 268);Ac-Nle-c[Asp-Phe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 269);Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 270);Ac-Nle-c[Asp-dTrp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 271 );Ac-Nle-c[Asp-dPhe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 272);Ac-Nle-c[Asp-dTyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 273);Ac-Nle-c[Asp-Trp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 274);Ac-Nle-c[Asp-Tyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 275);Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 276);Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 277);Ac-Nle-c[Glu-Pro-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 278);Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 279);Ac-Nle-c[Glu-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 280);Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 281 );Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 282);Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 283);Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 284);Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 285);Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 286);Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 287);Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 288);Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 289);Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 290);Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 291 );Ac-Nle-c[Asp-Phe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 292);Ac-Nle-c[Asp-Bip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 293);Ac-Nle-c[Asp-dHis-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 294);Ac-Nle-c[Asp-dTrp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 295);Ac-Nle-c[Asp-dPhe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 296);Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 297);Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 298);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 299);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2(SEQ ID NO: 300);Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 301 );Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 302);Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 303);Ac-Nle-c[Asp-Trp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 304);Ac-Nle-c[Asp-Tyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 305);Ac-Nle-c[Cys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 306);Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 307);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 308);Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 309);Ac-dl_ys-c[Asp-His-p(F)dPhe-Arg-Trp-l_ys]-dVal-dPro-NH2(SEQ ID NO: 310);Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 311 );Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 312);Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 313);Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 314);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 315);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 316);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 317);Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 318);Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 319);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 320);Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 321 );Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 322);Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 323);Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 324);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 325);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 326);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 327);Ac-Nle-c[Asp-Bip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 328);Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 329);Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 330);Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 331 );Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 332);Ac-Nle-c[Asp-Trp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 333);Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Phe-Lys]-dVal-dPro-NH2(SEQ ID NO: 334);Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 335);Ac-Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 336);Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 337);Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 338);Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 339);Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 340);Ac-Arg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 341 );Ac-dArg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 342);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 343);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2(SEQ ID NO: 344);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2(SEQ ID NO: 345);Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 346);Ac-Nle-c[dPen-dPhe-Arg-Trp-dPen]-dVal-dPro-NH2(SEQ ID NO: 347);Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 348);Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 349);Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 350);Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 351 ); andAc-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 352).

[0084] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein R4is dPhe or p(F)dPhe. Accordingly, in some embodiments, the sequence of Formula (I) is a sequence of Formula (IA):X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4-Y5-Y6-Y7(IA), wherein:X1is absent or selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis;X2is absent, Phe, or Nle;X3is absent, Phe, or Nle;R1is selected from the group consisting of Nle, dNIe, Ala, dAla, Arg, dArg, Lys, dLys, His, dHis, Orn, dOrn, dLeu, dTyr, Phe, dPhe, Trp, dTrp, Asp, Cys, and dCys;R2is selected from the group consisting of Asp, dAsp, Glu, Cys, dCys, dPen, Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, and dTyr;R3is absent or selected from the group consisting of His, Ala, Pro, Hyp, Leu, dGIn, Phe, dPhe, Trp, dTrp, Tyr, dTyr, Aba, Ata, Ala, Ate, APO, APPC, Tic, Bip, Oic, Che, loc, and Cpe;R4is dPhe or p(F)dPhe;R5is selected from the group consisting of Arg, His, c / sPra(guan), and fransPro(guan);R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, dNal(2’), Nal(2’), and Nal(1 ’);R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, and Orn;R8is absent or Lys;Y1is absent or selected from the group consisting of Vai, dVal, ]32-Val, P3-Val, Pro, dPro, P-Pro, Hyp, dHyp, dLeu, dTle, Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, Asn, dAsn, and dThr;Y2is absent or selected from the group consisting of Vai, dVal, p2-Val, P3-Val, Pro, dPro, dTle, p-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn;Y3is absent or selected from the group consisting of Vai, dVal, Pro, dPro, dThr, and dLys;Y4is absent or selected from the group consisting of dVal, dPro, and dAsp;Y5is absent or dVal;Y6is absent or dVal;Y7is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1and R7are each independently Cys or dCys; a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn.

[0085] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA):X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4-Y5-Y6-Y7(IA), wherein:X1is absent or selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis;X2is absent, Phe, or Nle;X3is absent, Phe, or Nle;R1is selected from the group consisting of Nle, dNIe, Ala, dAla, Arg, dArg, Lys, dLys, His, dHis, Orn, dOrn, dLeu, dTyr, Phe, dPhe, Trp, dTrp, Asp, Cys, and dCys;R2is selected from the group consisting of Asp, dAsp, Glu, Cys, dCys, dPen, Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, and dTyr;R3is absent or selected from the group consisting of His, Ala, Pro, Hyp, Leu, dGIn, Phe, dPhe, Trp, dTrp, Tyr, dTyr, Aba, Ata, Ala, Ate, APO, APPC, Tic, Bip, Oic, Che, loc, and Cpe;R4is dPhe or p(F)dPhe;R5is selected from the group consisting of Arg, His, c / sPra(guan), and f / 'ansPro(guan);R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, dNal(2’), Nal(2’), and Nal(1 ’);R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, and Orn;R8is absent or Lys;Y1is absent or selected from the group consisting of Vai, dVal, £2-Val, P3-Val, Pro, dPro, p-Pro, Hyp, dHyp, dLeu, dTle, Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, Asn, dAsn, and dThr;Y2is absent or selected from the group consisting of Vai, dVal, P2-Val, p3-Val, Pro, dPro, dTle, 0-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn;Y3is absent or selected from the group consisting of Vai, dVal, Pro, dPro, dThr, and dLys;Y4is absent or selected from the group consisting of dVal, dPro, and dAsp;Y5is absent or dVal;Y6is absent or dVal;Y7is absent or dPro; andthe non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1and R7are each independently Cys or dCys; a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn, provided that: when R4is p(F)dPhe, then (i) R3is selected from Pro, dGIn, and dTyr, R6is Trp, and R2is not Cys; or (ii) R3is His and R6is Nal(2’) or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2and R7; when R4is dPhe and R1is Asp, then either (i) R2is selected from Trp, Phe, His, Tyr, dPhe, dHis, and dTyr, R3is selected from Pro, Ala, and Leu, R5is Arg, and R6is selected from Trp, Nal( 1 ’), dNal(2’), and Nal(2’); or (ii) R2is selected from Ala, dAla, and Phe, and R3is His, wherein when R2is dAla, then Y1-Y7are absent and when R2is Ala, then R1is not Nle; when R4is dPhe, and R2is Asp, Glu, or dPen, then R3is not His or absent; and when R4is dPhe, R2is Asp, and R3is Pro, then R5is not dNal(2’) or Nal(2’) and Y3-Y7are absent if any of X1-X3are present.

[0086] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA):X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4-Y5-Y6-Y7(IA), wherein:X1is absent or selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis;X2is absent, Phe, or Nle;X3is absent, Phe, or Nle;R1is selected from the group consisting of Nle, dNIe, Ala, dAla, Arg, dArg, Lys, dLys, His, dHis, Orn, dOrn, dLeu, dTyr, Phe, dPhe, Trp, dTrp, Asp, Cys, and dCys;R2is selected from the group consisting of Asp, dAsp, Glu, Cys, dCys, dPen, Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, and dTyr;R3is absent or selected from the group consisting of His, Ala, Pro, Hyp, Leu, dGIn, Phe, dPhe, Trp, dTrp, Tyr, dTyr, Aba, Ata, Ala, Ate, APO, APPC, Tic, Bip, Oic, Che, loc, and Cpe;R4is dPhe or p(F)dPhe;R5is selected from the group consisting of Arg, His, c / sPra(guan), and f / 'ansPro(guan);R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, dNal(2’), Nal(2’), and Nal(1 ’);R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, and Orn;R8is absent or Lys;Y1is absent or selected from the group consisting of Vai, dVal, £2-Val, P3-Val, Pro, dPro, p-Pro, Hyp, dHyp, dLeu, dTle, Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, Asn, dAsn, and dThr;Y2is absent or selected from the group consisting of Vai, dVal, P2-Val, p3-Val, Pro, dPro, dTle, 0-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn;Y3is absent or selected from the group consisting of Vai, dVal, Pro, dPro, dThr, and dLys;Y4is absent or selected from the group consisting of dVal, dPro, and dAsp;Y5is absent or dVal;Y6is absent or dVal;Y7is absent or dPro; andthe non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1and R7are each independently Cys or dCys; a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:Ac-Nle-c[Asp-dTrp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 295);Ac-Nle-c[Asp-dPhe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 296);Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 297);Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 298);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 299);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2(SEQ ID NO: 300);Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 301 );Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 302);Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 303);Ac-Nle-c[Asp-Trp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 304);Ac-Nle-c[Asp-Tyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 305);Ac-Nle-c[Cys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 306);Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 307);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 308);Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 309);Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 310);Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 311 );Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 312);Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 313);Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 314);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 315);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 316);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 317);Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 318);Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 319);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 320);Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 321 );Ac-dl_ys-c[Asp-His-p(F)dPhe-Arg-Trp-l_ys]-dTle-dPro-NH2(SEQ ID NO: 322);Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 323);Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 324);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 325);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 326);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 327);Ac-Nle-c[Asp-Bip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 328);Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 329);Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 330);Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 331 );Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 332);Ac-Nle-c[Asp-Trp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 333);Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Phe-Lys]-dVal-dPro-NH2(SEQ ID NO: 334);Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 335);Ac-Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 336);Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 337);Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 338);Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 339);Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 340);Ac-Arg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 341 );Ac-dArg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 342);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 343);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2(SEQ ID NO: 344);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2(SEQ ID NO: 345);Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 346);Ac-Nle-c[dPen-dPhe-Arg-Trp-dPen]-dVal-dPro-NH2(SEQ ID NO: 347);Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 348);Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 349);Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 350);Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 351 ); andAc-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 352).

[0087] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IA), wherein R4is dPhe. In further embodiments, the sequence of Formula (I) or (IA) is cyclized between R2and R7or R8. Accordingly, in some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (IA(i)):X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4-Y5-Y6-Y7(IA(i)), wherein:X1is absent or Nle;X2is absent or Nle;X3is absent or Nle;R1is selected from the group consisting of Nle, dNIe, Ala, dAla, Arg, dArg, Lys, dLys, His, dHis, Orn, dOrn, dLeu, dTyr, Phe, dPhe, Trp, and dTrp;R2is selected from the group consisting of Asp, dAsp, Glu, Cys, dCys, and dPen;R3is absent or selected from the group consisting of Ala, Pro, Hyp, Leu, dGIn, Phe, dPhe, Trp, dTrp, Tyr, dTyr, Aba, Ata, Aia, Ate, APC, APPC, Tic, Bip, Oic, Che, loc, and Cpe;R4is dPhe;R5is selected from the group consisting of Arg, His, c / sPra(guan), and fra / ?sPro(guan);R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, and Nal(1 ’);R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, and Orn;R8is absent or Lys;Y1is absent or selected from the group consisting of Vai, dVal, £2-Val, P3-Val, Pro, dPro, P-Pro, Hyp, dHyp, dLeu, dTle, Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, Asn, dAsn, and dThr;Y2is absent or selected from the group consisting of Vai, dVal, £2-Val, £3-Val, Pro, dPro, dTle, 0-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn;Y3is absent or selected from the group consisting of Vai, dVal, Pro, dPro, dThr, and dLys;Y4is absent or selected from the group consisting of dVal, dPro, and dAsp;Y5is absent or dVal;Y6is absent or dVal;Y7is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of:a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R2and R7or R8when R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn.

[0088] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(i)):X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4-Y5-Y6-Y7(IA(i)), wherein:X1is absent or Nle;X2is absent or Nle;X3is absent or Nle;R1is selected from the group consisting of Nle, dNIe, Ala, dAla, Arg, dArg, Lys, dLys, His, dHis, Orn, dOrn, dLeu, dTyr, Phe, dPhe, Trp, and dTrp;R2is selected from the group consisting of Asp, dAsp, Glu, Cys, dCys, and dPen;R3is absent or selected from the group consisting of Ala, Pro, Hyp, Leu, dGIn, Phe, dPhe, Trp, dTrp, Tyr, dTyr, Aba, Ata, Aia, Ate, APC, APPC, Tic, Bip, Oic, Che, loc, and Cpe;R4is dPhe;R5is selected from the group consisting of Arg, His, c / sPra(guan), and f / 'ansPro(guan);R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, and Nal(1 ’);R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, and Orn;R8is absent or Lys;Y1is absent or selected from the group consisting of Vai, dVal, ]32-Val, P3-Val, Pro, dPro, P-Pro, Hyp, dHyp, dLeu, dTle, Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, Asn, dAsn, and dThr;Y2is absent or selected from the group consisting of Vai, dVal, p2-Val, P3-Val, Pro, dPro, dTle, p-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn;Y3is absent or selected from the group consisting of Vai, dVal, Pro, dPro, dThr, and dLys;Y4is absent or selected from the group consisting of dVal, dPro, and dAsp;Y5is absent or dVal;Y6is absent or dVal;Y7is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R2and R7or R8when R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn, provided that: when R2is Asp, Glu, or dPen, then R3is not absent; and when R2is Asp and R3is Pro, then Y3-Y7are absent if any of X1-X3are present.

[0089] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(i)), wherein:X1is absent or Nle;X2is absent or Nle;X3is absent or Nle;R1is selected from the group consisting of Nle, dNIe, Ala, dAla, Arg, dArg, Lys, dLys, His, dHis, Orn, dOrn, dLeu, dTyr, Phe, dPhe, Trp, and dTrp;R2is selected from the group consisting of Asp, dAsp, Glu, Cys, dCys, and dPen;R3is absent or selected from the group consisting of Ala, Pro, Hyp, Leu, dGIn, Phe, dPhe, Trp, dTrp, Tyr, dTyr, Aba, Ata, Aia, Ate, APC, APPC, Tic, Bip, Oic, Che, loc, and Cpe;R4is dPhe;R5is selected from the group consisting of Arg, His, c / sPra(guan), and fra / ?sPro(guan);R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, and Nal(1 ’);R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, and Orn;R8is absent or Lys;Y1is absent or selected from the group consisting of Vai, dVal, £2-Val, P3-Val, Pro, dPro, P-Pro, Hyp, dHyp, dLeu, dTle, Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, Asn, dAsn, and dThr;Y2is absent or selected from the group consisting of Vai, dVal, £2-Val, £3-Val, Pro, dPro, dTle, 0-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn;Y3is absent or selected from the group consisting of Vai, dVal, Pro, dPro, dThr, and dLys;Y4is absent or selected from the group consisting of dVal, dPro, and dAsp;Y5is absent or dVal;Y6is absent or dVal;Y7is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of:a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R2and R7or R8when R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence of:Ac-Nle-c[dPen-dPhe-Arg-Trp-dPen]-dVal-dPro-NH2(SEQ ID NO: 347); orAc-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 352).

[0090] Alternatively, in some embodiments, when the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IA), wherein R4is dPhe, then the sequence of Formula (I) or (IA) is cyclized between R1and R7. Accordingly, in some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (IA(ii)):X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IA(ii)), wherein:X1is absent or selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis;X2is absent, Phe, or Nle;X3is absent or Phe;R1is selected from the group consisting of Asp, Cys, and dCys;R2is selected from the group consisting of Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, and dTyr;R3is absent or selected from the group consisting of His, Pro, Ala, and Leu;R4is dPhe;R5is Arg;R6is selected from the group consisting of Trp, dNal(2’), Nal(2’), and Nal( 1 ’);R7is selected from the group consisting of Lys, Cys, and dCys;Y1is absent or selected from the group consisting of dVal, dLeu, dTle, dArg, and dLys;Y2is absent or selected from the group consisting of dVal, dPro, and dHyp;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1and R7are each independently Cys or dCys; and a lactam bridge between R1and R7when R1is Asp and R7is Lys.

[0091] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(ii)) :X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IA(ii)), wherein:X1is absent or selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis;X2is absent, Phe, or Nle;X3is absent or Phe;R1is selected from the group consisting of Asp, Cys, and dCys;R2is selected from the group consisting of Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, and dTyr;R3is absent or selected from the group consisting of His, Pro, Ala, and Leu;R4is dPhe;R5is Arg;R6is selected from the group consisting of Trp, dNal(2’), Nal(2’), and Nal( 1 ’);R7is selected from the group consisting of Lys, Cys, and dCys;Y1is absent or selected from the group consisting of dVal, dLeu, dTle, dArg, and dLys;Y2is absent or selected from the group consisting of dVal, dPro, and dHyp;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1and R7are each independently Cys or dCys; and a lactam bridge between R1and R7when R1is Asp and R7is Lys, provided that: when R1is Asp, then either (i) R2is selected from Trp, Phe, His, Tyr, dPhe, dHis, and dTyr, R3is selected from Pro, Ala, and Leu, R5is Arg, and R6is selected from Trp, Nal(1 ’), dNal(2’), and Nal(2’); or (ii) R2is selected from Ala, dAla, and Phe, and R3is His, wherein when R2is dAla, then Y1-Y7are absent and when R2is Ala, then R1is not Nle.

[0092] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(ii)), wherein:X1is absent or selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis;X2is absent, Phe, or Nle;X3is absent or Phe;R1is selected from the group consisting of Asp, Cys, and dCys;R2is selected from the group consisting of Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, and dTyr;R3is selected from the group consisting of His, Pro, Ala, and Leu;R4is dPhe;R5is Arg;R6is selected from the group consisting of Trp, dNal(2’), Nal(2’), and Nal( 1 ’);R7is selected from the group consisting of Lys, Cys, and dCys;Y1is absent or selected from the group consisting of dVal, dLeu, dTle, dArg, and dLys;Y2is absent or selected from the group consisting of dVal, dPro, and dHyp;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1and R7are each independently Cys or dCys; and a lactam bridge between R1and R7when R1is Asp and R7is Lys, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:Ac-Nle-c[Asp-Trp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 333);Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Phe-Lys]-dVal-dPro-NH2(SEQ ID NO: 334);Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 335); andAc-Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 336).

[0093] In some embodiments, when the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IA), wherein R4is p(F)dPhe. Accordingly, in some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (IA(iii)) :X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IA(iii)), wherein:X1is absent or Nle;R1is selected from the group consisting of Nle, Ala, Arg, dArg, Lys, dLys, His, and dHis;R2is selected from the group consisting of Asp, Glu, Cys, and dCys;R3is selected from the group consisting of His, Pro, dGIn, and dTyr;R4is p(F)dPhe;R5is Arg or His;R6is Trp or Nal(2’);R7is selected from the group consisting of Lys, Cys, dCys, and Orn;Y1is selected from the group consisting of dVal, dPro, and dTle;Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7, when R2and R7are each independently Cys or dCys; a lactam bridge between R2and R7when R2is Asp and R7is Lys; and a lactam bridge between R2and R7when R2is Asp, or Glu and R7is Orn.

[0094] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(iii)) :X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IA(iii)), wherein:X1is absent or Nle;R1is selected from the group consisting of Nle, Ala, Arg, dArg, Lys, dLys, His, and dHis;R2is selected from the group consisting of Asp, Glu, Cys, and dCys;R3is selected from the group consisting of His, Pro, dGIn, and dTyr;R4is p(F)dPhe;R5is Arg or His;R6is Trp or Nal(2’);R7is selected from the group consisting of Lys, Cys, dCys, and Orn;Y1is selected from the group consisting of dVal, dPro, and dTle;Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7, when R2and R7are each independently Cys or dCys; a lactam bridge between R2and R7when R2is Asp and R7is Lys; and a lactam bridge between R2and R7when R2is Asp, or Glu and R7is Orn, provided that: when R3is selected from Pro, dGIn, and dTyr, R6is Trp, then R2is not Cys; and when R3is His, then R6is Nal(2’) or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2and R7.

[0095] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(iii)), wherein:X1is absent or Nle;R1is selected from the group consisting of Nle, Ala, Arg, dArg, Lys, dLys, His, and dHis;R2is selected from the group consisting of Asp, Glu, Cys, and dCys;R3is selected from the group consisting of His, Pro, dGIn, and dTyr;R4is p(F)dPhe;R5is Arg or His;R6is Trp or Nal(2’);R7is selected from the group consisting of Lys, Cys, dCys, and Orn;Y1is selected from the group consisting of dVal, dPro, and dTle;Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7, when R2and R7are each independently Cys or dCys; a lactam bridge between R2and R7when R2is Asp and R7is Lys; and a lactam bridge between R2and R7when R2is Asp, or Glu and R7is Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 297);Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 298);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 299);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2(SEQ ID NO: 300);Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 301 );Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 302);Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 303);Ac-Nle-c[Cys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 306);Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 307);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 308);Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 309);Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 310);Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 311 );Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 312);Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 313);Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 314);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 315);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 316);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 317);Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 318);Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 319);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 320);Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 321 );Ac-dl_ys-c[Asp-His-p(F)dPhe-Arg-Trp-l_ys]-dTle-dPro-NH2(SEQ ID NO: 322);Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 323);Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 324);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 325);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 326); andAc-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 327).

[0096] In some embodiments, when the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein R4is p(CI)dPhe or p(Br)dPhe. When R4is p(CI)dPhe or p(Br)dPhe in the sequence of Formula (I), then R8is absent. Accordingly, in some embodiments, the sequence of Formula (I) is a sequence of Formula (IB):X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IB), wherein:X1is absent or Nle;R1is selected from the group consisting of Nle, Arg, dArg, Lys, dLys, His, and dHis;R2is Asp or dCys;R3is selected from the group consisting of His, Aba, Aia, and Ata;R4is p(CI)dPhe or p(Br)dPhe;R5is Arg;R6is Trp;R7is selected from the group consisting of Lys, Cys, and dCys;Y1is selected from the group consisting of dVal, dPro, and dTle;Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7, when R2and R7are each independently Cys or dCys; and a lactam bridge between R2and R7when R2is Asp and R7is Lys.

[0097] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB):X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IB), wherein:X1is absent or Nle;R1is selected from the group consisting of Nle, Arg, dArg, Lys, dLys, His, and dHis;R2is Asp or dCys;R3is selected from the group consisting of His, Aba, Aia, and Ata;R4is p(CI)dPhe or p(Br)dPhe;R5is Arg;R6is Trp;R7is selected from the group consisting of Lys, Cys, and dCys;Y1is selected from the group consisting of dVal, dPro, and dTle;Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7, when R2and R7are each independently Cys or dCys; and a lactam bridge between R2and R7when R2is Asp and R7is Lys, provided that: when R4is p(Br)dPhe, then R2is dCys; and when R4is p(CI)dPhe, then (i) R3is selected from Ata, Aia, and Aba; or (ii) R3is His, R5is Arg; R6is Trp; R7is Lys or dCys, and R1is not Ala, wherein when X1is present, then Y1is dTle and when X1is absent and Y1-Y2is dVal-dPro or dTle-dPro, then either R1is not Nle or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2and R7.

[0098] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB), wherein:X1is absent or Nle;R1is selected from the group consisting of Nle, Arg, dArg, Lys, dLys, His, and dHis;R2is Asp or dCys;R3is selected from the group consisting of His, Aba, Aia, and Ata;R4is p(CI)dPhe or p(Br)dPhe;R5is Arg;R6is Trp;R7is selected from the group consisting of Lys, Cys, and dCys;Y1is selected from the group consisting of dVal, dPro, and dTle;Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; andthe non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7, when R2and R7are each independently Cys or dCys; and a lactam bridge between R2and R7when R2is Asp and R7is Lys, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 234);Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2(SEQ ID NO: 238);Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 239);Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 240);Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 241 );Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 250);Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 251 );Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 252);Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 253);Ac-dl_ys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 254);Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 255);Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 256);Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 257);Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 258);Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 259);Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 260);Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 261 );Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 262);Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 263);Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 264);Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 279);Ac-Nle-c[Glu-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 280);Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 281 );Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 288);Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 289);Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 290); andAc-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 291 ).

[0099] In some embodiments, when the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IA), wherein R4is dPhe or p(F)dPhe. In further embodiments, the sequence of Formula (I) or (IA) is cyclized through a lactam bond between Asp or Glu at R2and Orn at R7. Accordingly, in some embodiments, the sequence of Formula (I) is a sequence of Formula (IC):R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IC), wherein:R1is Nle;R2is Asp or Glu;R3is Pro;R4is p(F)dPhe or dPhe;R5is Arg;R6is Trp;R7is Orn;Y1is dVal;Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7.

[0100] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC):R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IC), wherein:R1is Nle;R2is Asp or Glu;R3is Pro;R4is p(F)dPhe or dPhe;R5is Arg;R6is Trp;R7is Orn;Y1is dVal;Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7, provided that: when R4is dPhe, then R2is Glu.

[0101] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC), wherein:R1is Nle;R2is Asp or Glu;R3is Pro;R4is p(F)dPhe or dPhe;R5is Arg;R6is Trp;R7is Orn;Y1is dVal;Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 23).

[0102] In some embodiments, the non-naturally occurring melanocortin analog has one or more beta hairpin (P-hairpin) and / or beta turn (P-turn) structures. In some embodiments, the presence of Pro, dPro, Hyp, dHyp, fransPro(guan), and / or c / sPro(guan), provides the P-hairpin and / or p-turn structures of the non-naturally occurring melanocortin analog. In some embodiments, the disulfide bond of the sequence according to Formula (I), if present, provides the p-hairpin and / or p-turn structures of the non-naturally occurring melanocortin analog.

[0103] As will be appreciated by the skilled artisan, non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (l)-(IC), have an N-terminus and a C-terminus. The melanocortin analogs of the present technology are written beginning with the N-terminus at the left-most amino acid residue and ending with the C-terminus at the right most residue. Accordingly, the N-terminus of a non- naturally melanocortin analog comprising a sequence of any one of Formulae (l)-(IC) may be at any of X1, X2, X3, and R1. Analogously, the C-terminus of a non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (l)-(IC) may be at any of R7, R8, Y1, Y2, Y3, Y4, Y5, Y6, and Y7.

[0104] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog is modified by an acyl group. In some embodiments, the acyl group is acetyl group

[0105] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog is not modified.

[0106] As discussed above, Y1Y2Y3Y4Y5Y6Y7represents a C-terminus of the non- naturally occurring melanocortin analog. In some embodiments, Y1-Y7are absent. In some embodiments, Y1is present and Y2-Y7are absent. In some embodiments, Y1andY2are present and Y3-Y7are absent. In some embodiments, Y1-Y3are present and Y4- Y7are absent. In some embodiments, Y1-Y4are present and Y5-Y7are absent. In some embodiments, Y1-Y5are present and Y6-Y7are absent. In some embodiments, Y1- Y6are present and Y7is absent. In some embodiments, Y1-Y7are present.

[0107] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an amide groupthe sequence of any one of Formulae (l)-(ID), a non-naturally occurring melanocortin analog with a C-terminus modified by an amide may be represented by a terminal -NH2.

[0108] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified. In the sequence of any one of Formulae (l)-(l D), a non-naturally occurring melanocortin analog with an unmodified C-terminus may be represented by -OH.

[0109] Non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (l)-(IC) are cyclized. For example, the non-naturally occurring melanocortin analog may be cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1and R7are each independently Cys or dCys; a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn.

[0110] In some embodiments of the sequence of Formula (I), R4is Phe or dPhe. In further embodiments, R1is Nle, R3is Pro or His, R5is Arg, R6is Trp, Y1is dVal and Y2is dPro. In some embodiments, the sequence of Formulae (I) is: Ac-Nle-c[Asp-Pro-Phe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 2);Ac-Nle-c[Asp-Pro-His-Phe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 3); andAc-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 31 ), wherein c represents cyclization through R1or R2and R7via a lactam bond.

[0111] In some embodiments of the sequence of any one of Formulae (I )-( IC), R4is dPhe. In further embodiments, sequence of any one of Formulae (l)-(IC) is cyclized through a lactam bond between Asp R2and Lys at R7.

[0112] In some embodiments, X1-X3are absent. Alternatively, in some embodiments, one or more of , X1-X3is present. In some embodiments, X1is present and X2-X3are absent. In some embodiments, X1-X2are present and X3is absent. In some embodiments, X1-X3are present. In further embodiments, R1is Nle, R3is Pro, R5is Arg, R6is Trp, Y1is dVal or dTle and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of:Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 53);Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 40);Ac-Nle-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 188); andAc-Nle-Nle-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 189), wherein c represents cyclization through R2and R7via a lactam bond.

[0113] In some embodiments, R1is Nle. Alternatively, in some embodiments, R1is an amino acid other than Nle. In further embodiments, R1is selected from dLeu, dAla, Ala, dPhe, Phe, Trp, dTrp, dArg, Arg, dLys, His, dHis, Orn, and dOrn. In still further embodiments, R3is Pro, R5is Arg, and R6is Trp. In some embodiments, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of:Ac-dl_eu-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 66);Ac-dAla-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 94);Phe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 144);His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 145);Trp-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 147); dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 148); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 149); dTrp-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 150);Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 151 );Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 152);Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 153);Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 154);Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 155);Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 156);Ac-Orn-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 158);Ac-dOrn-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 159);Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 187);Ac-dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 193); andAc-dTyr-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 195), wherein c represents cyclization through R2and R7via a lactam bond.

[0114] In other embodiments, Y1is dTle and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of: Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 167);Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 168);Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 169);Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 170);Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 171 );Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 172); andAc-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 173), wherein c represents cyclization through R2and R7via a lactam bond.

[0115] In still other embodiments, Y1is selected from dArg, dLys, dVal, and dTle, Y2is selected from dPro, dVal, and dHyp, Y3is absent, dVal, or dPro, and Y4is absent or dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of:Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2(SEQ ID NO: 39);Ac-dl_ys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2(SEQ ID NO: 160);Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 161 );Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH2(SEQ ID NO: 162);Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2(SEQ ID NO: 163);Ac-Orn-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 164); andAc-dOrn-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 165), wherein c represents cyclization through R2and R7via a lactam bond.

[0116] In some embodiments, R3is Pro. Alternatively, in some embodiments, R3is an amino acid other than Pro. In further embodiments, R3is selected from Aba, Aia, Ata, APC, APPC, loc, Tyr, Trp, Ate, Ala, Leu, Hyp, Phe, dPhe, dGIn, dTyr, dTrp, Bip, Tic, Cpe, Che, and Oic. In still further embodiments, R1is Nle, R5is Arg, R6is Trp, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)- (IC) is selected from the group consisting of:Ac-Nle-c[Asp-Aba-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 4);Ac-Nle-c[Asp-Aia-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 5);Ac-Nle-c[Asp-Ata-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Nle-c[Asp-APC-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 10);Ac-Nle-c[Asp-APPC-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 1 1 );Ac-Nle-c[Asp-loc-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 18);Ac-Nle-c[Asp-Trp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 42);Ac-Nle-c[Asp-Tyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 43);Ac-Nle-c[Asp-Atc-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 63);Ac-Nle-c[Asp-Ala-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 88);Ac-Nle-c[Asp-Hyp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 142);Ac-Nle-c[Asp-dPhe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 174);Ac-Nle-c[Asp-dGln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 175);Ac-Nle-c[Asp-dTrp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 176);Ac-Nle-c[Asp-dTyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 177);Ac-Nle-c[Asp-Cpe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 190);Ac-Nle-c[Asp-Che-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 191 );Ac-Nle-c[Asp-Oic-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 192);Ac-Nle-c[Asp-Leu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 220);Ac-Nle-c[Asp-Tic-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 221 );Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 222); andAc-Nle-c[Asp-Bip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 223), wherein c represents cyclization through R2and R7via a lactam bond.

[0117] In some embodiments, R5is Arg. Alternatively, in some embodiments, R5is an amino acid other than Arg. In further embodiments, R5is selected from tra / ?sPro(guan), cZsPro(guan), and His. In still further embodiments, when R1is Nle, R3is Pro, R6is Trp, R7is Lys, Y1is dVal, and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of:Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 12);Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 13); andAc-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 92), wherein c represents cyclization through R2and R7via a lactam bond.

[0118] In some embodiments, R6is Trp. Alternatively, in some embodiments, R6is an amino acid other than Trp. In further embodiments, R6is selected from Aia, Aba, Ata, dTrp, Nal(1 ’), and Phe. In still further embodiments, when R1is Nle, R3is Pro, R5is Arg, R7is Lys, Y1is dVal, and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of:Ac-Nle-c[Asp-Pro-dPhe-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 14);Ac-Nle-c[Asp-Pro-dPhe-Arg-Aba-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15);Ac-Nle-c[Asp-Pro-dPhe-Arg-Ata-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2(SEQ ID NO: 65);Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(1 ’)-Lys]-dVal-dPro-NH2(SEQ ID NO: 95); andAc-Nle-c[Asp-Pro-dPhe-Arg-Phe-Lys]-dVal-dPro-NH2(SEQ ID NO: 96),wherein c represents cyclization through R2and R7via a lactam bond.

[0119] In some embodiments, Y1is dVal, Y2is dPro, and the C-terminus is modified by NH2. Alternatively, in some embodiments, Y1is an amino acid other than dVal, Y2is an amino acid other than dPro, and / or the C-terminus is not modified. In further embodiments Y1is selected from dThr, dPro, Vai, P-Val, Hyp, dHyp, Pro, (3-Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, Lys, dLys, and dTle and Y2is selected from dThr, dVal, Vai, p-Val, Hyp, dHyp, Pro, p-Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, and dTle. In still further embodiments, R1is Nle, R3is Pro, R5is Arg, and R6is Trp. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of:Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Hyp-NH2 (SEQ ID NO: 36);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 37);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-p2Val-pPro-NH2 (SEQ ID NO: 38);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-NH2 (SEQ ID NO: 41 );Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 44);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-Pro-Val-NH2 (SEQ ID NO: 45);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 46);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-Pro-Val-NH2 (SEQ ID NO: 47);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-Val-Pro-NH2 (SEQ ID NO: 48);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 49);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 50);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 51 );Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 52);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Trp-NH2 (SEQ ID NO: 54);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dAsn-NH2(SEQ ID NO: 57);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asn-dPro-NH2 (SEQ ID NO: 58);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Ala-Ala-NH2(SEQ ID NO: 59);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Gly-Gly-NH2(SEQ ID NO: 60);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsn-dPro-NH2 (SEQ ID NO: 61 );Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Val-Pro-NH2(SEQ ID NO: 104);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Val-NH2(SEQ ID NO: 129);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dThr-dPro-dThr-NH2(SEQ ID NO: 130);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dThr-dPro-dThr-OH (SEQ ID NO: 131 );Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2(SEQ ID NO: 132);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-dPro-dVal-NH2(SEQ ID NO: 133);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-pPro-p2Val-NH2(SEQ ID NO: 134);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-pPro-p3Val-NH2(SEQ ID NO: 135);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 136);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-p3Val-pPro-NH2(SEQ ID NO: 137);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Pro-NH2(SEQ ID NO: 138);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-pPro-pPro-NH2(SEQ ID NO: 139);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Arg-NH2(SEQ ID NO: 146);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dArg-NH2(SEQ ID NO: 157);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2(SEQ ID NO: 166);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH2(SEQ ID NO: 178);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-Val-Pro-NH2(SEQ ID NO: 179);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dVal-dPro-NH2(SEQ ID NO: 180);Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 181 );Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2(SEQ ID NO: 182);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2(SEQ ID NO: 183);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2(SEQ ID NO: 184);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 185);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2(SEQ ID NO: 186);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dPro-dVal-NH2(SEQ ID NO: 197);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAla-dAla-NH2(SEQ ID NO: 198);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asp-NH2(SEQ ID NO: 199);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dHyp-NH2(SEQ ID NO: 200);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Asp-NH2(SEQ ID NO: 201 );Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Hyp-NH2(SEQ ID NO: 203);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asp-dPro-NH2(SEQ ID NO: 204);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asn-NH2(SEQ ID NO: 205);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsp-NH2(SEQ ID NO: 206);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsn-NH2(SEQ ID NO: 207);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dPro-NH2(SEQ ID NO: 208);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 209);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 17), wherein c represents cyclization through R2and R7via a lactam bond.

[0120] In some embodiments, R4is dPhe and the sequence of any one of Formulae (l)-(IC) is cyclized through a lactam bond between Glu or Asp at R2and Orn at R7. In some embodiments, the sequence of any one of Formulae ( l)-(IC) is: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 23); orAc-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 216), wherein c represents cyclization through R2and R7via a disulfide bond.

[0121] In some embodiments, R4is dPhe and the sequence of any one of Formulae ( l)-(IC) is cyclized through a disulfide bond between R2and R7, where R2and R7are each independently selected from Cys, dCys, and dPen. In further embodiments, R1is Nle, R3is Pro or absent, R5is Arg, R6is Trp, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae ( l)-(IC) is selected from the group consisting of:Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 62);Ac-Nle-c[dPen-Pro-dPhe-Arg-Trp-dPen]-dVal-dPro-NH2(SEQ ID NO: 67);Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-dCys]-dVal-dPro-NH2(SEQ ID NO: 74);Ac-Nle-c[Cys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 202); andAc-Nle-c[Cys-dPhe-Arg-Trp-Pen]-dVal-dPro-NH2(SEQ ID NO: 210), wherein c represents cyclization through R2and R7via a disulfide bond.

[0122] In some embodiments, R4is dPhe and the sequence of any one of Formulae ( l)-(IC) is cyclized through a lactam or disulfide bond between R1and R7. In some embodiments, R2is Trp and / or R3is Pro. In further embodiments, X1is selected from Nle, Ala, Lys, dLys, Arg, His, and dHis; R2is selected from Trp, Phe, His, Tyr, dPhe, dHis, and dTyr; R3is selected from Pro, Ala, and Leu, R5is Arg, and R6is selected from Trp, dNal(2’), Nal(2’), and Nal( 1 '). In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of:Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 64);Ac-Nle-c[Cys-Trp-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 99);Ac-Nle-c[dCys-Trp-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 100);Ac-Nle-c[dCys-Trp-Pro-dPhe-Arg-Trp-dCys]-dVal-dPro-NH2(SEQ ID NO: 101 );Ac-Ala-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 102);Ac-Lys-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 103);Ac-dLys-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 105);Ac-Arg-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 106);Ac-dArg-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 107);Ac-dHis-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 108);Ac-His-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 109);Ac-Nle-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 1 10);Ac-Nle-c[Asp-Trp-Ala-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 1 11 );Ac-Nle-c[Asp-Trp-Leu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 1 12);Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Nal(1 ')-Lys]-dVal-dPro-NH2(SEQ ID NO: 113);Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 114);Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 115);Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2(SEQ ID NO: 1 16);Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2(SEQ ID NO: 1 17);Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2(SEQ ID NO: 1 18);Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH2(SEQ ID NO: 1 19);Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2(SEQ ID NO: 120);Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 121 );Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 122);Ac-Nle-c[Asp-Phe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 123);Ac-Nle-c[Asp-His-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 124);Ac-Nle-c[Asp-Tyr-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 125);Ac-Nle-c[Asp-dPhe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 126);Ac-Nle-c[Asp-dHis-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 127); andAc-Nle-c[Asp-dTyr-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 128), wherein c represents cyclization through R1and R7via a lactam bond.

[0123] In other embodiments, R2is Ala or dAla and R3is His. In further embodiments, X1is Arg or dArg; R5is Arg, and R6is Trp, Y1is absent or dVal, and Y2is absent or dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of:Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 194);Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 196); andAc-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 230), wherein c represents cyclization through R1and R7via a lactam bond.

[0124] In still other embodiments, R2is Phe and R3is His. In further embodiments, X1is Nle or Phe; R5is Arg, and R6is Trp, Y1is selected from dVal, dLeu, and dTle, and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of:Ac-Nle-Phe-Phe-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 140);Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 141 );Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dLeu-dPro-NH2(SEQ ID NO: 224); andAc-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 225), wherein c represents cyclization through R1and R7via a lactam bond.

[0125] In some embodiments, R4is dPhe and the sequence of any one of Formulae ( l)-(IC) is cyclized through a lactam or disulfide bond between R2and R8. In some embodiments, R7is Pro or Gly. In further embodiments, R1is Nle R3is Pro or Hyp, R5is Arg, and R6is Trp. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of:Ac-Nle-c[Asp-Hyp-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2(SEQ ID NO: 143);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dVal-dPro-NH2(SEQ ID NO: 55);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dPro-dPro-dLys-dAsp-NH2(SEQ ID NO: 56);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2(SEQ ID NO: 219); wherein c represents cyclization through R2and R8via a lactam bond.

[0126] In some embodiments of the sequence of any one of Formulae (I )-( IC), R4is p(F)dPhe. In further embodiments, sequence of any one of Formulae (l)-(IC) is cyclized through a lactam bond between Asp R2and Lys at R7.

[0127] In some embodiments, X1-X3are absent. Alternatively, in some embodiments, one or more of , X1is present and X2-X3are absent. In further embodiments, R1is Nle, R3is Pro, R5is Arg, R6is Trp, Y1is dVal or dTle and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of:Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 20);Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 76); andAc-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 77), wherein c represents cyclization through R2and R7via a lactam bond.

[0128] In some embodiments, R1is Nle. Alternatively, in some embodiments, R1is an amino acid other than Nle. In further embodiments, R1is selected from Ala, Arg, dArg, dLys, His, and dHis. In still further embodiments, R3is Pro, R5is Arg, and R6isTrp. In some embodiments, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of: Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 213);Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 214);Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 215);Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 68);Ac-dl_ys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 69);Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 70); andAc-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 71 ), wherein c represents cyclization through R2and R7via a lactam bond.

[0129] In other embodiments, Y1is dTle and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of: Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 78);Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 79);Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 80);Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 81 );Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 82);Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 83); andAc-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 84), wherein c represents cyclization through R2and R7via a lactam bond.

[0130] In some embodiments, R3is Pro. Alternatively, in some embodiments, R3is an amino acid other than Pro. In further embodiments, R3is selected from His, dGIn and dTyr. In still further embodiments, R1is Nle, R5is Arg, R6is Trp or dNal(2’), Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)- (IC) is selected from the group consisting of:Ac-Nle-c[Asp-dGln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 97);Ac-Nle-c[Asp-dTyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 98); andAc-Nle-c[Asp-His-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2(SEQ ID NO: 226),wherein c represents cyclization through R2and R7via a lactam bond.

[0131] In some embodiments, R5is Arg. Alternatively, in some embodiments, R5is an amino acid other than Arg. In further embodiments, R5is His. In some embodiments, the sequence of any one of Formulae (l)-(IC) is: Ac-Nle-c[Asp-Pro- p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 21 ), wherein c represents cyclization through R2and R7via a lactam bond.

[0132] In some embodiments, R1is Nle, R3is Pro, R5is Arg, and R6is Trp. In further embodiments, Y1is selected from dVal, dPro and dTle, Y2is selected from dVal, dPro, and dTle, Y3is absent, dVal, or dPro, and Y4is absent or dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of:Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 19);Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 22);Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2(SEQ ID NO: 72);Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 73); andAc-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 75), wherein c represents cyclization through R2and R7via a lactam bond.

[0133] In some embodiments, R4is p(F)dPhe and the sequence of any one of Formulae (l)-(IC) is cyclized through a lactam bond between Glu or Asp at R2and Orn at R7. In some embodiments, the sequence of any one of Formulae ( l)-(IC) is: Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 217); orAc-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 218), wherein c represents cyclization through R2and R7via a disulfide bond.

[0134] In some embodiments, R4is p(F)dPhe and the sequence of any one of Formulae ( l)-(IC) is cyclized through a disulfide bond between R2and R7, where R2and R7are each independently Cys or dCys. In further embodiments, R1is Nle, R3is Pro or His, R5is Arg, R6is Trp, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of: Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 211 );Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2(SEQ ID NO: 212);Ac-Nle-c[dCys-His-p(F)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2(SEQ ID NO: 93);Ac-Nle-c[Cys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 227); andAc-Nle-c[dCys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 231 ), wherein c represents cyclization through R2and R7via a disulfide bond.

[0135] In some embodiments of the sequence of any one of Formulae (l)-(IC), R4is p(CI)dPhe or p(Br)dPhe. In further embodiments, sequence of any one of Formulae (l)-(IC) is cyclized through a lactam bond between Asp R2and Lys at R7.

[0136] In some embodiments, R1is Nle. Alternatively, in some embodiments, R1is an amino acid other than Nle. In further embodiments, R1is selected from Arg, dArg, dLys, His, and dHis. In still further embodiments, R3is His, R4is p(CI)dPhe, R5is Arg, and R6is Trp. In some embodiments, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of: Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 24);Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 25);Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 26);Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 27);Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 86); andAc-dl_ys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 87), wherein c represents cyclization through R2and R7via a lactam bond.

[0137] In other embodiments, Y1is dTle and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of: Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 33);Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 34);Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 35);Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 228);Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 229); andAc-dl_ys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 89),wherein c represents cyclization through R2and R7via a lactam bond.

[0138] In some embodiments, R3is Pro. Alternatively, in some embodiments, R3is an amino acid other than Pro. In further embodiments, R3is selected from Aia, Aba, and Ata. In still further embodiments, R1is Nle, R5is Arg, R6is Trp, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of: Ac-Nle-c[Asp-Aba-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Nle-c[Asp-Aia-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 8); anAc-Nle-c[Asp-Ata-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 9), wherein c represents cyclization through R2and R7via a lactam bond.

[0139] In some embodiments, Y1is dVal and Y2is dPro. Alternatively, in some embodiments, Y1is an amino acid other than dVal and / or Y2is an amino acid other than dPro. In further embodiments, R1is Nle, R5is Arg, and R6is Trp. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2(SEQ ID NO: 28);Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 29);Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 30); andAc-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 32), wherein c represents cyclization through R2and R7via a lactam bond.

[0140] In some embodiments, R4is p(CI)dPhe or p(Br)dPhe and the sequence of any one of Formulae (l)-(IC) is cyclized through a disulfide bond between R2and R7, where R2and R7are each independently Cys or dCys. In further embodiments, R1is Nle, R3is Pro or His, R5is Arg, R6is Trp, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IC) is selected from the group consisting of:Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2(SEQ ID NO: 85);Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 90); andAc-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2(SEQ ID NO: 91 ), wherein c represents cyclization through R2and R7via a disulfide bond.

[0141] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2- 231 .

[0142] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 4- 6, 10-23, 31 , 36-84, 88, 92-227, 230, and 231.

[0143] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(i)). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 4- 6, 10-18, 23, 31 , 36-63, 65-67, 74, 88, 92, 94-96, 104, 129-139, 142-193, 195, 197-210, 216, and 219-223.

[0144] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(ii)). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 64, 99-103, 105-128, 140, 141 , 194, 196, 145, 147, and 230.

[0145] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(iii)). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 19-22, 68-73, 75-84, 93, 97, 98, 211 -215, 217, 218, 226, 227, and 231 .

[0146] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 7- 9, 24-30, 32-35, 85-87, 89-91 , 228, and 229.

[0147] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 216-218.Non-Naturally Occurring Melanocortin Analog Synthesis

[0148] The non-naturally occurring melanocortin analogs of the present technology may be readily synthesized by any known conventional procedure for the formation of a peptide linkage between amino acids. Such conventional procedures include, for example, any solution phase procedure permitting a condensation between the free alpha amino group of an amino acid or residue thereof having the carboxyl group or other reactive groups protected and the free primary carboxyl group of another amino acid or residue thereof having the amino group or other reactive groups protected. In an exemplary procedure, the peptides of the present technology may be synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare the peptides of the present technology.

[0149] The process for synthesizing the peptides may be carried out by a procedure whereby each amino acid in the desired sequence is added one at a time in succession to another amino acid or residue thereof or by a procedure whereby peptide fragments with the desired amino acid sequence are first synthesized conventionally and then condensed to provide the desired peptide. The resulting peptide is then cyclized to yield a cyclic peptide.

[0150] Solid phase peptide synthesis methods are well known and practiced in the art. In such methods, the synthesis of peptides may be carried out by sequentially incorporating the desired amino acid residues one at a time into the 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).

[0151] In chemical syntheses of peptides, reactive side chain groups of the various amino acid residues are protected with suitable protecting groups, which prevent a chemical reaction from occurring at that site until the protecting group is removed. Also common is the protection of the alpha amino group of an amino acid residue or fragment while that entity reacts at the carboxyl group, followed by the selective removal of the alpha amino protecting group to allow a subsequent reaction to take place at that site.Specific protecting for solid phase synthesis methods and solution phase synthesis methods groups are known to those having ordinary skill in the art.

[0152] Alpha amino groups may be protected by a suitable protecting group, including a urethane-type protecting group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p-chlorobenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-biphenyl-isopropoxycarbonyl, 9- fluorenylmethoxycarbonyl (Fmoc) and p-methoxybenzyloxycarbonyl (Moz); aliphatic urethane-type protecting groups, such as t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc is useful for alpha amino protection.

[0153] Guanidino groups may be protected by a suitable protecting group, such as nitro, p-toluenesulfonyl (Tosyl), Z, pentamethylchromanesulfonyl (Pmc), adamantyloxycarbonyl, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and Boc. Pmc is a useful protecting group for Arg.

[0154] Solid phase synthesis is commenced from the C-terminal end of the peptide by coupling a protected alpha amino acid to a suitable resin. Such starting material is prepared by attaching an alpha amino-protected amino acid by an ester linkage to a p- benzyloxybenzyl alcohol (Wang) resin or a 2-chlorotrityl chloride resin, by an amide bond between an Fmoc-Linker, such as p-[(R,S)-a-[1-(9H-fluor-en-9-yl)- methoxyformamido]-2,4-dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) to a benzhydrylamine (BHA) resin, or by other means well known in the art. Fmoc-Linker- BHA resin supports are commercially available and generally used when feasible. The resins are carried through repetitive cycles as necessary to add amino acids sequentially. The alpha amino Fmoc protecting groups are removed under basic conditions. Piperidine, piperazine, diethylamine, or morpholine (20-40% v / v) in N,N- dimethylformamide (DMF) may be used for this purpose.

[0155] Following removal of the alpha amino protecting group, the subsequent protected amino acids are coupled stepwise in the desired order to obtain an intermediate, protected peptide-resin. The activating reagents used for coupling of the amino acids in the solid phase synthesis of the peptides are well known in the art. After the peptide is synthesized, if desired, the orthogonally protected side chain protectinggroups may be removed using methods well known in the art for further derivatization of the peptide.

[0156] Reactive groups in a peptide may be selectively modified, either during solid phase synthesis or after removal from the resin. For example, peptides may be modified to obtain N-terminus modifications, such as acetylation, while on resin, or may be removed from the resin by use of a cleaving reagent and then modified. Methods for N-terminus modification, such as acetylation, and for C-terminus modification, such as amidation, are known in the art. Similarly, methods for modifying side chains of amino acids are well known to those skilled in the art of peptide synthesis. The choice of modifications made to reactive groups present on the peptide will be determined, in part, by the characteristics that are desired in the peptide.

[0157] The peptide may be cyclized prior to cleavage from the peptide resin. For cyclization through reactive side chain moieties, the desired side chains are deprotected, and the peptide suspended in a suitable solvent and a cyclic coupling agent added. Suitable solvents include, for example DMF, dichloromethane (DCM) or1 -methyl-2-pyrrolidone (NMP). Suitable cyclic coupling reagents include, for example,2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1 -yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1 -yl-oxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2- (7-aza-1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TATU), 2- (2-oxo-1 (2H)-pyridyl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TPTU) or N,N'- dicyclohexylcarbodiimide / 1 -hydroxybenzotriazole (DCCI / HOBt). Coupling is convention initiated by use of a suitable base, such as N,N-diispropylethylamine (DIPEA), sym- collidine or N-methylmorpholine (NMM).

[0158] Following cleavage of peptides from the solid phase following their synthesis, the peptide may be purified by any number of methods, such as reverse phase high performance liquid chromatography (RP-HPLC), using a suitable column, such as a C18 column. Other methods of separation or purification, such as methods based on the size or charge of the peptide, may also be employed. Once purified, the peptide may be characterized by any number of methods, such as high-performance liquid chromatograph (HPLC), amino acid analysis, mass spectrometry, and the like.Salt Forms of Non-Naturally Occurring Melanocortin Analogs

[0159] The non-naturally occurring melanocortin analog peptides of the present technology may be in the form of any salt. The term “pharmaceutically acceptable salts” refers to salts prepared from non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Exemplary salts are the ammonium, calcium, lithium, magnesium, potassium, and sodium salts. Salts derived from organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0160] When the non-naturally occurring melanocortin analogs of the present technology are basic, acid addition salts may be prepared from non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, carboxylic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, trifluoroacetic acid, and the like. Acid addition salts of the peptides of the present technology are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, citric, tartaric, maleic, succinic or methanesulfonic acid. The acetate salt form is especially useful. Where the peptides of the present technology include an acidic moiety, suitable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.Conjugates

[0161] The present technology further includes conjugates comprising a non- naturally occurring melanocortin analog. In some embodiments, the non-naturally melanocortin analog is conjugated to a pharmaceutical agent. Non-limiting examples of suitable pharmaceutical agents include peptides, monoclonal antibodies, and small molecules. In yet other embodiments, the non-naturally occurring melanocortin analog is conjugated to a small molecule MCR agonist.

[0162] Conjugates of the present technology further comprise a linker connecting the non-naturally occurring melanocortin analog to the pharmaceutical agent. In some embodiments, the linker is rigid. In some embodiments, the linker is flexible. In some embodiments, the linker is a cleavable linker. In some embodiments, the linker comprises a glycine-serine (Gly / Ser) linker, a proline-threonine-glycine linker, an alanine linker, a lysine linker, a threonine linker, a valine-glycine-serine-threonine linker, an elastin-like peptide linker, a hexahistidine linker, a polyethylene glycol linker, a fatty acid linker, or a hydrocarbon linker.

[0163] In some embodiments, the linker is a peptide linker. The peptide linkers of the present technology may vary from 2 to 31 amino acids of any primary sequence in length and do not impose any constraints on the conformation or interactions of the linked partners. In some embodiments, the linkers vary from about 2-30, 2-29, 2-28, 2- 27, 2-26, 2-25, 2-24, 2-23, 2-22, 2-21 , 2-20, 2-19, 2-18, 2-17, 2-16, 2-15, 2- 14, 2-13, 2-12, 2-1 1 , 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-31 , 3-30, 3-29, 3-28, 3-27, 3-26, 3- 25, 3-24, 3-23, 3-22, 3-21 , 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-1 1 , 3- 10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-31 , 4-30, 4-29, 4-28, 4-27, 4-26, 4-25, 4-24, 4-23, 4-22, 4-21 , 4- 20, 4-19, 4-18, 4-17, 4-16, 4-15, 4-14, 4-13, 4-12, 4-1 1 , 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-31 , 5- 30, 5-29, 5-28, 5-27, 5-26, 5-25, 5-24, 5-23, 5-22, 5-21 , 5-20, 5-19, 5- 18, 5-17, 5-16, 5-15, 5- 14, 5-13, 5-12, 5-1 1 , 5-10, 5-9, 5-8, 5-7, 5-6, 6-31 , 6-30, 6-29, 6-28, 6-27, 6-26, 6-25, 6-24, 6-23, 6-22, 6-21 , 6-20, 6-19, 6-18, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12, 6-1 1 , 6-10, 6-9, 6-8, 6- 7, 7-31 , 7-30, 7-29, 7-28, 7-27, 7-26, 7-25, 7-24, 7-23, 7-22, 7-21 , 7-20, 7-19, 7-18, 7-17, 7- 16, 7-15, 7-14, 7-13, 7-12, 7-11 , 7-10, 7-9, 7- 8, 8-31 , 8-30, 8-29, 8-28, 8-27, 8-26, 8-25, 8-24, 8-23, 8-22, 8-21 , 8-20, 8-19, 8-18, 8- 17, 8-16, 8-15, 8-14, 8-13, 8-12, 8-11 , 8-10, 8-9, 9-31 , 9-30, 9-29, 9-28, 9-27, 9-26, 9- 25, 9-24, 9-23, 9-22, 9-21 , 9-20, 9-19, 9-18, 9-17, 9-16, 9-15, 9-14, 9-13, 9-12, 9-1 1 , 9-10, 10-31, 10-30, 10-29, 10-28, 10-27, 10-26, 10-25, 10-24, 10-23, 10-22, 10-21, IQ-20, 10-19, 10-18, 10-17, 10-16, 10-15, 10-14, 10-13, 10-12, 10-11, 11-31, 11-30, 11-29, 11-28, 11-27, 11-26, 11-25, 11-24, 11-23, 11-22, 11-21, 11-20, 11-19, 11-18, IT-17, 11-16, 11-15, 11-14, 11-13, 11-12, 12-31, 12-30, 12-29, 12-28, 12-27, 12-26, 12-25,12-24, 12-23, 12-22, 12-21, 12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 12-13, 13-31 , 13-30, 13-29, 13-28, 13-27, 13-26, 13-25, 13-24, 13-23, 13-22, 13-21 , 13-20, 13- 19, 13-18, 13-17, 13-16, 13-15, 13-14, 14-31, 14-30, 14-29, 14-28, 14-27, 14-26, 14-25, 14-24, 14-23, 14-22, 14-21, 14-20, 14-19, 14-18, 14-17, 14-16, 14-15, 15-31, 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-31, 16-30, 16-29, 16-28, 16-27, 16-26, 16-25, 16-24, 16-23, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-31, 17-30, 17-29, 17-28, 17-27, 17-26, 17-25, 17-24, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-31, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 18-19, 19-31, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-31, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-31, 21-30, 21-29, 21-28, 21- 27, 21-26, 21-25, 21-24, 21-23, 21-22, 22-31, 22-30, 22-29, 22-28, 22-27, 22-26, 22-25, 22-24, 22-23, 23-31, 23-30, 23-29, 23-28, 23-27, 23-26, 23-25, 23-24, 24-31, 24-30, 24-29, 24-28, 24-27, 24-26, 24-25, 25-31, 25-30, 25-29, 25-28, 25-27, 25-26, 26-31, 26-30, 26-29, 26-28, 26-27, 27-31, 27-30, 27-29, 27-28, 28-31, 28-30, 28-29, 29- 31 , 29-30, or 30-31 amino acids of any primary sequence in length. The peptide linkers may be designed as appropriate for an intended use.

[0164] The peptide linkers may comprise one or more of a Gly-rich linker (e.g., a flexible linker connecting various domains in a single protein without interfering with the function of each domain; a linker forming stable covalently linked dimers; a linker to connect two independent domains that create a ligand-binding site or recognition sequence), a Serine linker (e.g., a coiled structure linker); a coiled structure linker comprising a Gin, Arg, Glu, Ser, and / or Pro amino acids; a rigid space linker comprising one or more of a Pro, Arg, Phe, Thr, Glu, and / or Gin residues; a linker comprising a flexible Gly-rich regions that may may generate loops connecting domains; or a linker comprising a Thr, Ser, Gly, and / or Ala residue.

[0165] In some embodiments, the linker comprises an amino acid sequence about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 100% identical to the amino acid sequence of any one of Linker A, LinkerB, Linker C, Linker D, Linker E, Linker F, Linker G, Linker H, Linker I, Linker J, Linker K, Linker L, Linker M, Linker N, Linker O, Linker P, Linker Q, Linker R, or Linker S in Table 0.

[0166] In some embodiments, the linker comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 100% identical to the amino acid sequence of any one of Linker A, Linker B, Linker C, Linker D, Linker E, Linker F, Linker G, Linker H, Linker I, Linker J, Linker K, Linker L, Linker M, Linker N, Linker O, Linker P, Linker Q, Linker R, or Linker S in Table 0.In some embodiments, the linker comprises an amino acid sequence at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 100% identical to the amino acid sequence of any one of Linker A, Linker B, Linker C, Linker D, Linker E, Linker F, Linker G, Linker H, Linker I, Linker J, Linker K, Linker L, Linker M, Linker N, Linker O, Linker P, Linker Q, Linker R, or Linker S in Table 0.Table 0: Peptide Linker Amino Acid SequencesPharmaceutical Compositions

[0167] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology are present in a pharmaceutical composition.

[0168] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the composition. For example, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration 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 a total volume of the composition. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the pharmaceutical composition.

[0169] In some embodiments, the non-naturally occurring melanocortin analog comprises any one of SEQ ID NOs: 31 , 216, and 218, and the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the pharmaceutical composition. For example, the non-naturally occurring melanocortin analog comprising any one of SEQ ID NOs: 31 , 216, and 218is present in the pharmaceutical composition in a concentration 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 a total volume of the pharmaceutical composition. In some embodiments, the non-naturally occurring melanocortin analog comprising any one of SEQ ID NOs: 31 , 216, and 218 is present in the pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the pharmaceutical composition.

[0170] In some embodiments, the composition comprises the non-naturally occurring melanocortin analog of formula (I) at a concentration at 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 more, depending on the specific peptide selected, the desired response, the route of administration, the formulation and other factors known to those of skill in the art. In some embodiments, the non-naturally occurring melanocortin analog comprises any one of SEQ ID NOs: 31 , 216, and 218.

[0171] The non-naturally occurring melanocortin analogs may be formulated with one or more pharmaceutically acceptable carriers and / or excipients. The carriers and / or excipients of the present technology facilitate delivery of the non-naturally occurring melanocortin analog to a subject. Other pharmaceutically acceptable carriers and / or excipients may be included in the pharmaceutical composition to enhance dispersion, solubility, and / or stability of the non-naturally occurring melanocortin analog, and / or to reduce adverse injection site reactions.

[0172] In some embodiments, the pharmaceutical composition comprises 0.1 to 99.9999 wt.%, 1 to 99.999 wt.%, 5 to 99.99 wt.%, 10 to 99.9 wt.%, 15 to 99 wt.%, 20 to 90 wt.%, 30 to 85 wt.%, 40 to 80 wt.%, 50 to 75 wt.%, or 60 to 70 wt.% of the pharmaceutically acceptable carrier and / or excipient relative to a total weight of the pharmaceutical composition.

[0173] In some embodiments, the pharmaceutically acceptable carrier and / or excipient of the pharmaceutical composition is selected from the group consisting of water, a buffer, an inorganic salt, a fatty acid, a vegetable oil, a synthetic fatty ester, a surfactant, and a polymer.

[0174] In some embodiments, the pharmaceutically acceptable carrier and / or excipient of the pharmaceutical composition is water. In some embodiments, the pharmaceutically acceptable carrier and / or excipient of the pharmaceutical composition is a buffer.

[0175] In some embodiments, the pharmaceutical composition contains about 0.1 to about 99.9999 wt.%, about 1 to about 99.999 wt.%, about 5 to about 99.99 wt.%, about 10 to about 99.9 wt.%, about 15 to about 99 wt.%, about 20 to about 90 wt.%, about 30 to about 85 wt.%, about 40 to about 80 wt.%, about 50 to about 75 wt.%, or about 60 to about 70 wt.% of one or more pharmaceutically acceptable carriers and / or excipients relative to a total weight of the pharmaceutical composition.

[0176] In some embodiments, the pharmaceutical composition contains at least 0.1 to at least 99.9999 wt.%, at least 1 to at least 99.999 wt.%, at least 5 to at least 99.99 wt.%, at least 10 to at least 99.9 wt.%, at least 15 to at least 99 wt.%, at least 20 to at least 90 wt.%, at least 30 to at least 85 wt.%, at least 40 to at least 80 wt.%, at least 50 to at least 75 wt.%, or at least 60 to at least 70 wt.% of one or more pharmaceutically acceptable carriers and / or excipients relative to a total weight of the pharmaceutical composition.

[0177] In some embodiments, the pharmaceutical composition contains at least about 0.1 to at least about 99.9999 wt.%, at least about 1 to at least about 99.999 wt.%, at least about 5 to at least about 99.99 wt.%, at least about 10 to at least about 99.9 wt.%, at least about 15 to at least about 99 wt.%, at least about 20 to at least about 90 wt.%, at least about 30 to at least about 85 wt.%, at least about 40 to at least about 80 wt.%, at least about 50 to at least about 75 wt.%, or at least about 60 to at least about 70 wt.% of one or more pharmaceutically acceptable carriers and / or excipients relative to a total weight of the pharmaceutical composition.

[0178] Any pharmaceutically acceptable carriers and / or excipients known in the art may be included in the pharmaceutical composition. Non-limiting examples of pharmaceutically acceptable carriers and / or excipients include buffers, binders,excipients, stabilizers, lubricants, oils, adjuvants, preservatives, lipids, and antioxidants. The pharmaceutical composition may comprise any combination of the one or more pharmaceutically acceptable carriers and / or excipients previously described in relation to the first and pharmaceutical compositions. In some embodiments, the one or more pharmaceutically acceptable carriers and / or excipients comprise water.

[0179] The carriers and / or excipients of the composition may generally include 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 tonicity adjustors, (v) one or more surfactants, (vi) flavor, (vii) propellants, and / or (viii) a vehicle or solvent. In some embodiments, all components are compatible with the non-naturally occurring melanocortin analog (i.e., do not react or cause the non-naturally occurring melanocortin analog to react) and are homogeneously dispersed or dissolved uniformly in the composition.

[0180] In some embodiments, the one or more pharmaceutically acceptable carriers and / or excipients are isotonic. In some embodiments, the carrier and / or excipient is isotonic to nasal fluids.

[0181] In some embodiments, the pharmaceutical composition further comprises a pharmaceutical salt. Any pharmaceutical salt known in the art may be included in the pharmaceutical composition. For examples, to achieve a desirable tonicity, the pharmaceutical composition may include a salt selected from the group consisting of sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride.

[0182] In some embodiments, the salt is present in the pharmaceutical composition in a concentration of about 0.1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 25 mg / mL, or about 5 mg / mL to about 10 mg / mL, relative to a total volume of the composition.

[0183] In some embodiments, the salt is present in the pharmaceutical composition in a concentration of at least 0.1 mg / mL to at least 50 mg / mL, at least 1 mg / mL to at least 25 mg / mL, or at least 5 mg / mL to at least 10 mg / mL, relative to a total volume of the composition.

[0184] In some embodiments, the salt is present in the pharmaceutical composition in a concentration of at least about 0.1 mg / mL to at least about 50 mg / mL, at least about 1 mg / mL to at least about 25 mg / mL, or at least about 5 mg / mL to at least about 10 mg / mL, relative to a total volume of the composition.

[0185] Pharmaceutically acceptable carriers and / or excipients that may be included in the pharmaceutical composition generally include a pH buffered aqueous solution comprising one or more of the following components: (a) sodium acetate, (b) Tris, and (c) water. In some embodiments, all components are compatible with the non- naturally occurring melanocortin analog (i.e., do not react or cause the non-naturally occurring melanocortin analog to react) and are homogeneously dispersed or dissolved uniformly in the composition.

[0186] In the pH buffered solution of the pharmaceutical composition, the water may act as a diluent and include, without limitation, water for injection (WFI), sterile water, bacteriostatic water for injection (BWFI), distilled water, bidistilled water, deionized water, deionized distilled water, and reverse osmosis water. In some embodiments, the water present in the pH buffered aqueous solution is water for injection.

[0187] In some embodiments, the pharmaceutical composition includes water in an amount 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 a total weight of the composition.

[0188] In some embodiments, the pharmaceutical composition includes water in an amount of at least 1 wt% to at least 90 wt%, at least 10 wt% to at least 75 wt%, or at least 25 wt% to at least 50 wt%, relative to a total weight of the composition.

[0189] In some embodiments, the pharmaceutical composition includes water in an amount of at least about 1 wt% to at least about 90 wt%, at least about 10 wt% to at least about 75 wt%, or at least about 25 wt% to at least about 50 wt%, relative to a total weight of the composition.

[0190] In some embodiments, sodium acetate is present in the pharmaceutical composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, sodium acetate may be present in the pharmaceutical composition in a concentration of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2mg / 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 a total volume of the composition.

[0191] In some embodiments, sodium acetate is present in the pharmaceutical composition in a concentration of about 6 mg / mL to about 8 mg / mL, relative to a total volume of the composition. For example, sodium acetate may be present in the pharmaceutical composition in 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 a total volume of the composition.

[0192] In some embodiments, sodium acetate is present in the pharmaceutical composition in a molar concentration of 5 mM to 700 mM, relative to a total volume of the composition. For example, sodium acetate may be present in the pharmaceutical composition in 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 a total volume of the composition.

[0193] In some embodiments, sodium acetate is present in the pharmaceutical composition in a molar concentration of about 80 mM to about 100 mM, relative to a total volume of the composition. For example, sodium acetate may be present in the pharmaceutical composition in a molar concentration of 80 mM, 85 mM, 87 mM, 90 mM, 95 mM, or 100 mM, relative to a total volume of the composition.

[0194] The term “Tris” refers to tris(hydroxymethyl)aminomethane, which is also known as Tris buffer, Tris base, TRIS, tromethamine, tromethamine buffer, Trizma®, Trisamine, Trometamol, Tromethane, Trisaminol, or THAM. In some embodiments, Tris is present in the pharmaceutical composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, Tris may be present in the pharmaceutical composition in a concentration 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 a total volume of the composition.

[0195] In some embodiments, Tris is present in the pharmaceutical composition in a concentration of about 6 mg / mL to about 8 mg / mL, relative to a total volume of the composition. For example, Tris may be present in the pharmaceutical composition in 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 a total volume of the composition.

[0196] In some embodiments, Tris is present in the pharmaceutical composition in a molar concentration of 2 mM to 500 mM, relative to a total volume of the composition. For example, Tris may be present in the pharmaceutical composition in 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 a total volume of the composition.

[0197] In some embodiments, Tris is present in the pharmaceutical composition in a molar concentration of about 50 mM to about 70 mM, relative to a total volume of the composition. For example, Tris may be present in the pharmaceutical composition in a molar concentration of 50 mM, 55 mM, 60 mM, 65 mM, or 70 mM, relative to a total volume of the composition.

[0198] In some embodiments, the pH buffered aqueous solution provides the pharmaceutical composition with a pH equivalent or close to the physiological pH levels. This may reduce adverse injection site reactions and also provide the non-naturally occurring melanocortin analog with enhanced stability and resistance to aggregation and degradation.

[0199] In some embodiments, a weight ratio of sodium acetate to Tris is about 1 :4 to about 4:1 , about 2:7 to about 7:2, about 1 :3 to about 3:1 , about 2:5 to about 5:2, about 1 :2 to about 2:1 , about 2:3 to about 3:2, or about 1 :1 . In some embodiments, the weight ratio of sodium acetate to Tris is about 1 :1.

[0200] In some embodiments, a weight ratio of sodium acetate to Tris is at least 1 :4 to at least 4:1 , at least 2:7 to at least 7:2, at least 1 :3 to at least 3:1 , at least 2:5 to at least 5:2, at least 1 :2 to at least 2:1 , at least 2:3 to at least 3:2, or at least 1 :1 . In some embodiments, the weight ratio of sodium acetate to Tris is at least 1 :1 .

[0201] In some embodiments, a weight ratio of sodium acetate to Tris is at least about 1 :4 to at least about 4:1 , at least about 2:7 to at least about 7:2, at least about 1 :3 to at least about 3:1 , at least about 2:5 to at least about 5:2, at least about 1 :2 to at least about 2:1 , at least about 2:3 to at least about 3:2, or at least about 1 :1. In some embodiments, the weight ratio of sodium acetate to Tris is at least about 1 :1 .

[0202] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is about 1 :1 to about 20:1 , about 3:2 to about15:1 , about 2:1 to about 12:1 , about 3:1 to about 10:1 , about 4:1 to about 9:1 , about 5:1 to about 8:1 , or about 6:1 to about 7:1 . In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is about 7:1 .

[0203] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least 1 :1 to at least 20:1 , at least 3:2 to at least 15:1 , at least 2:1 to at least 12:1 , at least 3:1 to at least 10:1 , at least 4:1 to at least 9:1 , at least 5:1 to at least 8:1 , or at least 6:1 to at least 7:1 . In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least 7:1.

[0204] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least about 1 :1 to at least about 20:1 , at least about 3:2 to at least about 15:1 , at least about 2:1 to at least about 12:1 , at least about 3:1 to at least about 10:1 , at least about 4:1 to at least about 9:1 , at least about 5:1 to at least about 8:1 , or at least about 6:1 to at least about 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least about 7:1 .

[0205] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is about 1 :1 to about 20:1 , about 3:2 to about 15:1 , about 2:1 to about 12:1 , about 3:1 to about 10:1 , about 4:1 to about 9:1 , about 5:1 to about 8:1 , or about 6:1 to about 7:1. In some embodiments, the weight ratio of the non- naturally occurring melanocortin analog to Tris is about 7:1 .

[0206] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is at least 1 :1 to at least 20:1 , at least 3:2 to at least 15:1 , at least 2:1 to at least 12:1 , at least 3:1 to at least 10:1 , at least 4:1 to at least 9:1 , at least 5:1 to at least 8:1 , or at least 6:1 to at least 7:1 . In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is at least 7:1 .

[0207] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is at least about 1 :1 to at least about 20:1 , at least about 3:2 to at least about 15:1 , at least about 2:1 to at least about 12:1 , at least about 3:1 to at least about 10:1 , at least about 4:1 to at least about 9:1 , at least about 5:1 to at least about 8:1 , or at least about 6:1 to at least about 7:1 . In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is at least about 7:1 .

[0208] In addition to sodium acetate and T ris, the pharmaceutical composition may include other buffering agents. Non-limiting examples of additional buffering agents include saline, phosphate, phosphoric acid, citrate, succinate, gluconate, histidine, acetic acid, ascorbate, tartartic acid, maleic acid, glycine, lactate, lactic acid, ascorbic acid, imidazole, bicarbonate, carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, edetate, malate, imidazole, and mixtures thereof. In some embodiments, the pharmaceutical composition comprises acetic acid as an additional buffering agent.

[0209] The pharmaceutical composition may further comprise one or more chelating agents. Suitable chelating agents include, but are not limited to edetate disodium dihydrate, calcium disodium edetate, sodium edetate, calcium versetamide sodium, calteridol, and diethylenetriaminepentaacetic acid. In some embodiments, the pharmaceutical composition further comprises edetate disodium dihydrate.

[0210] The pharmaceutical composition may further comprise a preservative agent. Exemplary preservative agents include, but are not limited to, ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, phenol, m-cresol, benzyl alcohol, alpha-tocopherol, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, benzalkonium chloride, phenoxyethanol, and methyl paraben. In some embodiments, when the pharmaceutical composition comprises a preservative agent, the preservative agent is phenol, benzyl alcohol, or a combination thereof.

[0211] If present in the pharmaceutical composition, the concentration of the preservative agent may 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, relative to a total volume of the composition.

[0212] The pharmaceutical composition may further comprise an emulsifier. Nonlimiting examples of emulsifiers that may be included in the pharmaceutical composition include sodium carboxymethylcellulose, cetyl alcohol, glycerol monostearate, methylcellulose, and stearic acid. In some embodiments, when the pharmaceutical composition comprises an emulsifier, the emulsifier is sodium carboxymethylcellulose.

[0213] The pharmaceutical composition may further comprise a lipid. Lipids may enhance solubility and / or improve permeability of the non-naturally occurring melanocortin analog. In some embodiments, the lipid is a phospholipid. Non-limiting examples of phospholipids that may be included in the pharmaceutical composition include egg phosphatidylcholine, hydrogenated soybean phoshphaditylcholine, glycerophosphocholine, lecithin, and N-(carbonyl-methoxypolyethylene glycol 2000)- 1 ,2-distearoyl-glycero-3-phosphoethanolamine sodium salt. In some embodiments, when the pharmaceutical composition comprises a lipid, the lipid is N-(carbonyl- methoxypolyethylene glycol 2000)-1 ,2-distearoyl-glycero-3-phosphoethanolamine sodium salt

[0214] The pharmaceutical composition may further comprise a bulking agent. Inclusion of a bulking agent may increase the stability of the pharmaceutical composition. Non-limiting examples of bulking agents that may be included in the pharmaceutical composition include sucrose, lactose, trehalose, mannitol, sorbitol, glucose, raffinose, glycine, histidine, and polyvinyl pyrrolidone. In some embodiments, when the pharmaceutical composition comprises a bulking agent, the bulking agent is mannitol.

[0215] In some embodiments, the pharmaceutical composition is in the form of an aqueous solution or a suspension. In some embodiments, the pharmaceutical composition is in the form of an emulsion. In some embodiments, the pharmaceutical composition is in the form of an aqueous solution. In some embodiments, the pharmaceutical composition is in the form of an aqueous solution which is clear, colorless, and / or free of visible foreign matter.

[0216] In some embodiments, the pharmaceutical composition has a pH ranging from about 6.5 to about 8.5. In some embodiments, the pharmaceutical composition has a pH of 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.

[0217] In some embodiments, the pharmaceutical composition has a pH ranging from at least 6.5 to at least 8.5. In some embodiments, the pharmaceutical composition has a pH of at least 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.

[0218] In some embodiments, the pharmaceutical composition has a pH ranging from at least about 6.5 to at least about 8.5. In some embodiments, the pharmaceutical composition has a pH of at least about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 72, 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.

[0219] In some embodiments, the pharmaceutical composition is basic 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 pharmaceutical composition has a pH ranging from about 7.3 to about 7.4. In some embodiments, the pharmaceutical composition has a pH of 7.3 or7.4.

[0220] In some embodiments, the pharmaceutical composition is basic and has a pH of at least 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 pharmaceutical composition has a pH ranging from at least 7.3 to at least 7.4. In some embodiments, the pharmaceutical composition has a pH of 7.3 or 7.4.

[0221] In some embodiments, the pharmaceutical composition is basic and has a pH of at least 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, or8.5. In some embodiments, the pharmaceutical composition has a pH ranging from at least about 7.3 to at least about 7.4. In some embodiments, the pharmaceutical composition has a pH of 7.3 or 7.4.

[0222] In some embodiments, the pharmaceutical composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the pharmaceutical composition may have an osmolality ranging 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 pharmaceutical composition has an osmolarity of 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 pharmaceutical composition has an osmolality ranging from about 275 mOsm / kg to about 330 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about 279 mOsm / kg, about 314 mOsm / kg, or about 329 mOsm / kg.

[0223] In some embodiments, the pharmaceutical composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the pharmaceutical composition may have an osmolality ranging 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 at least 300 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolarity of at least 250 mOsm / kg, at least 260 mOsm / kg, at least 270 mOsm / kg, at least 280 mOsm / kg, at least 290 mOsm / kg, at least 300 mOsm / kg, at least 310 mOsm / kg, at least 320 mOsm / kg, at least 330 mOsm / kg, at least 340 mOsm / kg, at least 350 mOsm / kg, or at least 360 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality ranging from at least 275 mOsm / kg to at least 330 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least 279 mOsm / kg, at least 314 mOsm / kg, or at least 329 mOsm / kg.

[0224] In some embodiments, the pharmaceutical composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the pharmaceutical composition may have an osmolality ranging 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 at least about 300 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolarity of at least about 250 mOsm / kg, at least about 260 mOsm / kg, at least about 270 mOsm / kg, at least about 280 mOsm / kg, at least about 290 mOsm / kg, at least about 300 mOsm / kg, at least about 310 mOsm / kg, at least about 320 mOsm / kg, at least about 330 mOsm / kg, at least about 340 mOsm / kg, at least about 350 mOsm / kg, or at least about 360 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality ranging from at least about 275 mOsm / kg to at least about 330 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least about 279 mOsm / kg, at least about 314 mOsm / kg, or at least about 329 mOsm / kg.

[0225] In some embodiments, the pharmaceutical composition has a viscosity ranging from about 0.5 cP to about 5 cP. For example, the pharmaceutical composition may have a viscosity ranging from about 0.5 cP to about 5 cP, about 0.75 cP to about 4.5 cP, about 1 .0 cP to about 4 cP, about 1 .2 cP to about 3.5 cP, about 1 .3 cP to about 3 cP, about 1 .4 cP to about 2.5 cP, about 1 .5 cP to about 2 cP, or about 1 .6 cP to about 1 .8 cP. In some embodiments, the pharmaceutical composition has a viscosity of about0.5 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 pharmaceutical composition has a viscosity of about 1 .4 cP or about 1 .6 cP.

[0226] In some embodiments, the pharmaceutical composition has a viscosity ranging from at least 0.5 cP to at least 5 cP. For example, the pharmaceutical composition may have a viscosity ranging from at least 0.5 cP to at least 5 cP, at least 0.75 cP to at least 4.5 cP, at least 1 .0 cP to at least 4 cP, at least 1 .2 cP to at least 3.5 cP, at least 1 .3 cP to at least 3 cP, at least 1 .4 cP to at least 2.5 cP, at least 1 .5 cP to at least 2 cP, or at least 1.6 cP to at least 1.8 cP. In some embodiments, the pharmaceutical composition has a viscosity of at least 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 pharmaceutical composition has a viscosity of at least 1 .4 cP or at least 1 .6 cP.

[0227] In some embodiments, the pharmaceutical composition has a viscosity ranging from at least about 0.5 cP to at least about 5 cP. For example, the pharmaceutical composition may have a viscosity ranging from at least about 0.5 cP to at least about 5 cP, at least about 0.75 cP to at least about 4.5 cP, at least about 1 .0 cP to at least about 4 cP, at least about 1 .2 cP to at least about 3.5 cP, at least about 1 .3 cP to at least about 3 cP, at least about 1 .4 cP to at least about 2.5 cP, at least about 1 .5 cP to at least about 2 cP, or at least about 1 .6 cP to at least about 1 .8 cP. In some embodiments, the pharmaceutical composition has a viscosity of at least 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 pharmaceutical composition has a viscosity of at least about 1 .4 cP or at least about 1 .6 cP.

[0228] In some embodiments, the pharmaceutical composition disclosed is formulated for parenteral administration, such as, for example, in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. The term “parenteral,” as used herein, includes subcutaneous, intravenous, intraperitoneal, intramuscular, and intralesional, or infusion techniques.

[0229] When the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration), the active ingredient(s) (e.g., the non-naturally occurring melanocortin analog) may be dissolved or suspended in theaforementioned carrier and / or excipient. Additional aqueous or non-aqueous carriers that may facilitate 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 buffers.

[0230] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration) and comprises a non- naturally occurring melanocortin analog in a concentration 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 even more, depending on the specific peptide selected, the desired therapeutic response, the route of administration, the formulation and other factors known to those of skill in the art.

[0231] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration) and comprises sodium acetate in a concentration 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, 85 mM, 86 mM, 87 mM, 88 mM, 89 mM, 90 mM, 91 mM, 92 mM, 93 mM, 94 mM, 95 mM, 96 mM, 97 mM, 98 mM, 99 mM, 100 mM, 105 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM.

[0232] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration) and comprises Tris in a concentration of about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 3 5mM, 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, 1 10 mM, or 120 mM.

[0233] In some embodiments, the pharmaceutical composition comprises one or more antioxidants. For example, the pharmaceutical composition may comprise ascorbic acid, cysteine, sodium metabisulfite, propyl gallate, butylated hydroxytoluene, and / or butylated hydroxyanisole.

[0234] In some embodiments, the pharmaceutical composition comprises a surfactant, such as a sorbitan ester.

[0235] In some embodiments, the pharmaceutical composition comprises a flavoring or scent, such as an aromatic oil.

[0236] In some embodiments, the non-naturally occurring melanocortin analog is solubilized or suspended in a solvent or vehicle. The solvent or vehicle may be purified water, ethyl alcohol, and / or propylene glycol. In some embodiments, the pharmaceutical composition comprises between 0.03 wt% and 1 wt% melanocortin analog solubilized or suspended in a solvent or vehicle. For example, the pharmaceutical composition may comprise the non-naturally occurring melanocortin analog in an amount of about 0.03 wt%, about 0.05 wt%, about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.3 wt%, about 0.35 wt%, about 0.4 wt%, about 0.45 wt%, about 0.5 wt%, about 0.55 wt%, about 0.6 wt%, about 0.65 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.85 wt%, about 0.9 wt%, about 0.95 wt%, or about 1 wt%.

[0237] In some embodiments, the pharmaceutical composition may comprise the non-naturally occurring melanocortin analog in an amount of at least 0.03 wt%, at least 0.05 wt%, at least 0.1 wt%, at least 0.15 wt%, at least 0.2 wt%, at least 0.25 wt%, at least 0.3 wt%, at least 0.35 wt%, at least 0.4 wt%, at least 0.45 wt%, at least 0.5 wt%, at least 0.55 wt%, at least 0.6 wt%, at least 0.65 wt%, at least 0.7 wt%, at least 0.75 wt%, at least 0.8 wt%, at least 0.85 wt%, at least 0.9 wt%, at least 0.95 wt%, or at least 1 wt%.

[0238] In some embodiments, the pharmaceutical composition may comprise the non-naturally occurring melanocortin analog in an amount of at least about 0.03 wt%, at least about 0.05 wt%, at least about 0.1 wt%, at least about 0.15 wt%, at least about 0.2 wt%, at least about 0.25 wt%, at least about 0.3 wt%, at least about 0.35 wt%, at least about 0.4 wt%, at least about 0.45 wt%, at least about 0.5 wt%, at least about 0.55 wt%, at least about 0.6 wt%, at least about 0.65 wt%, at least about 0.7 wt%, at least about 0.75 wt%, at least about 0.8 wt%, at least about 0.85 wt%, at least about 0.9 wt%, at least about 0.95 wt%, or at least about 1 wt%.

[0239] The non-naturally occurring melanocortin analogs of the present technology may be formulated for administration using any means known in the art, including orally, rectally, vaginally, ocularly, intranasally, topically, parenterally, or by injection. If administered by injection, the peptide injection may be intravenous (IV), subcutaneous (SC), intramuscular (IM), intraperitoneal (IP), intracerebroventricular( IC V) , or other means known in the art. The non-naturally occurring melanocortin analog of the combination therapy may be formulated by any means known in the art, including but not limited to formulation as tablets, capsules, caplets, suspensions, powders, lyophilized preparations, suppositories, pessaries, ocular drops, skin patches, orally soluble formulations, enteric formulations, solutions sprays, aerosols and the like, and may be mixed and formulated with buffers, binders, excipients, stabilizers, lubricants, oils, adjuvants, anti-oxidants and other agents known in the art. In general, any route of administration by which the peptides are introduced across an epidermal layer of cells may be employed. Administration includes topical delivery. Administration includes delivery across the blood brain barrier. Administration includes delivery through mucous membranes, buccal administration, ophthalmic administration, oral administration, dermal administration, inhalation administration, nasal administration, urethral administration, vaginal administration, rectal administration, and the like.

[0240] In some embodiments, the pharmaceutical composition formulated for intranasal administration comprises a non-naturally occurring melanocortin analog at a concentration at 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 more, depending on the specific peptide selected, the desired therapeutic response, the route of administration, the formulation and other factors known to those of skill in the art.

[0241] In some embodiments, the pharmaceutical composition is formulated for oral administration. For example, the pharmaceutical composition may be in the form of a tablet, capsule, lozenge, pill, sachet, or any other orally deliverable form know in the art.

[0242] The composition may be formulated to be delivered by nose drop, spray device, or topical solution. In some embodiments, the pharmaceutical composition may be formulated as an aerosol, atomizer, inhalation, insufflation, metered-dose inhaler, or nebulizer. In some embodiments, the pharmaceutical composition includes a propellant, such as hydrofluoroalkane.

[0243] In some embodiments, the pharmaceutical composition may be configured to be administered using a spray device or nasal inhaler. The spray device or nasal inhaler may be configured to deliver 1 ug to 10Oug per spray. In some embodiments, thespray device or nasal inhaler may be configured to deliver 1 ug to 100ug, 5ug to 90ug, 1 Dug to 80ug, 15ug to 70ug, 20ug to 60ug, 25ug, to 50ug, or 30ug to 40ug per spray.Dosing

[0244] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered hourly once a day, or twice a day. In some embodiments, 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. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the pharmaceutical composition.Methods

[0245] The non-naturally occurring melanocortin analogs of the present technology may interact with one or more ligand binding sites of a melanocortin receptor, thereby modulating melanocortin receptor activity. This may modulate melanocortin receptor signaling pathways, including, but not limited to, reward and reinforcement-type pathways, thereby reducing pain, cravings, and / or withdrawal symptoms. As such, the non-naturally occurring melanocortin analog of the present technology may be useful pain management, opioid and other substance addictions (e.g., alcohol or nicotine addiction), or reducing a symptom thereof.

[0246] In some embodiments, the non-naturally occurring melanocortin analogs selectively bind at least a portion of an melanocortin receptor. The portion may comprise one or more amino acids of an melanocortin receptor. In some embodiments, the non- naturally occurring melanocortin analogs selectively bind two or more amino acids of an melanocortin receptor. The melanocortin receptor may be a MC3R or a MC4R.

[0247] The non-naturally occurring melanocortin analogs may comprise one or more motifs that confer binding to a melanocortin receptor or at least a portion thereof. The motif may be selected from the group consisting of Pro-p(F)dPhe; Trp-Pro- p(F)dPhe; dAla-Pro-p(F)dPhe; dAla-Pro-dPhe; Pro-dPhe; loc-dPhe; dAla-Pro-dPhe; Trp-Pro-dPhe; Pro-His-dPhe; His-p(CI)dPhe; Aba-p(CI)dPhe; Aia-p(CI)dPhe; Ata- p(CI)dPhe; Oic-p(F)dPhe; Oic-dPhe; dPhe at position R4; and p(F)dPhe at position R4.

[0248] The non-naturally occurring melanocortin analogs of the present technology may have a dissociation constant (Kd) value for an melanocortin receptor or one or more amino acids thereof that is less than that of a conventional melanocortin analog.Subjects

[0249] In some embodiments, the subject has used or is using an addictive substance. In some embodiments, the subject has used or is using a medication to treat an addiction. In some embodiments, the frequency or amount of the addictive substance and / or rescue medication is reduced during or after administration of the non-naturally occurring melanocortin analog. In some embodiments, the frequency or amount of the addictive substance and / or rescue medication is reduced as the dose or dosage of the non-naturally occurring melanocortin analog increases. In some embodiments, the frequency or amount of the addictive substance and / or rescue medication comprises a downward titration during or after administration of a non-naturally occurring melanocortin analog.

[0250] In some embodiments, the subject is a mammal, including but not limited to a human, a non-human primate such as a chimpanzee, a domestic livestock or a farm animal such as a cow, a bison, sheep, a pig, a goat, a horse, a chicken, and a rooster, a domestic pet animal such as a dog, a cat, a rat, a mouse, and a rabbit, and a laboratory subject such as a rodent, including a rat, a mouse, and a guinea pig. In some embodiments, the subject is a human. In some embodiments, the subject is an animal such as a rat or a dog.Controls

[0251] The controls of the present technology may comprise the subject at baseline. In some embodiments, the controls of the methods of the present technology comprise a subject that is not administered a non-naturally occurring melanocortin analog of the present technology or a subject subjected to a method lacking one or more steps of the methods of the present technology.Pharmacokinetics and Pharmacodynamics

[0252] The non-naturally occurring melanocortin analogs of the present technology exhibit pharmacokinetic (pK) and / or pharmacodynamic (pD) parameters.Such pK and / or pD may be expressed or otherwise determined relative to a control, which, in some instances, may be a non-naturally occurring melanocortin analog lacking one or more features of the non-naturally occurring melanocortin analogs of the present technology.

[0253] In some embodiments, the pK and / or pD of the non-naturally occurring melanocortin analogs may be assessed using concentration and / or temporal measurements (e.g., Ttmai, Cmax, T1 / z (h)), AUC, or Tmax. In some embodiments, the non- naturally occurring melanocortin analogs have reduced clearance and / or metabolism, increased uptake, absorption, and / or stability, relative to a control.Clearance

[0254] “Clearance” may refer to the elimination, absorption, and / or metabolism of the non-naturally occurring melanocortin analogs in the subject’s plasma. Clearance may be assessed as volume of plasma cleared of the non-naturally occurring melanocortin analogs over time (e.g., mL / min, L / hr, or L / day) and / or may be normalized to body weight of the subject (e.g., mL / min / kg). Reduced clearance may also be represented by an increase in half-life or volume of distribution (Vd). In some embodiments, measuring clearance comprises measuring a terminal elimination rate constant (Az) or an inter-compartmental clearance (Q).

[0255] In some embodiments, the reduction in clearance comprises a measurement 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 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0256] In some embodiments, the reduction in clearance comprises a measurement during administration of the non-naturally occurring melanocortin analogs. In some embodiments, the reduction in clearance comprises a measurement at the completion of administration of the non-naturally occurring melanocortin analogs.Concentration

[0257] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology comprise an increased tissue, plasma, and / or serum concentration relative to a control. “Concentration” may comprise a measurementreflecting one or more of the absolute amounts of the non-naturally occurring melanocortin analogs, the absorption of the non-naturally occurring melanocortin analogs, the metabolism of non-naturally occurring melanocortin analogs, or the elimination of non-naturally occurring melanocortin analogs.

[0258] The increased tissue, plasma, and / or serum concentration may be an increase in concentration of the non-naturally occurring melanocortin analogs at a given time point relative to a control administered at the same dose and measured at the same time point. The concentration may be measured at an intermediate time point or a final time point and may be measured as a mean residence time (MRT), an average concentration (Cavg), a trough concentration (Ctrough), or a concentration at the end of administration (e.g., infusion) time (CT).

[0259] In some embodiments, the increased concentration is reflected by an increase in peak plasma concentration (Cmax). An increase in Cmax may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control. In some embodiments, Cmax comprises a dose normalized Cmax (DNCmax).

[0260] In some embodiments, the increased concentration is reflected by an increase in minimum plasma concentration (Cmin). An increase in Cmin may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control. In some embodiments, Cmin comprises a dose normalized Cmin (DNCmin).

[0261] In some embodiments, the increased concentration is reflected by a reduction in time to reach Cmax (Tmax). A reduced Tmax may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control.

[0262] In some embodiments, the increased concentration is reflected by a final measurable concentration (Ttinai) . An increased Ttinai may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control.

[0263] In some embodiments, the increased concentration is reflected by an increase in area under the curve (AUC). An increase in AUC may signify increasedexposure to the non-naturally occurring melanocortin analogs and / or may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control. The AUC measurement may comprise an Area Under the Curve for Concentration of Drug in Non-Compartmental Analysis (DNAUC).

[0264] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement 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 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0265] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement 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 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0266] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement 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 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0267] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement during administration of the non-naturally occurring melanocortin analogs.

[0268] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement at the completion of administration of the non- naturally occurring melanocortin analogs.

[0269] In some embodiments, the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is at least about 5 ng / mL to at least about 2000 ng / mL about 24 hours after administration of the non-naturally occurring melanocortin analog.

[0270] In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject until the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is at least about 5 ng / mL to at least about 2000 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 5 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 10 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 50 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 100 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 200 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 300 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 400 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 500 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the wherein concentration is at least about 750 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 1000 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the is at least about 1500 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 2000 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is a Cmax.Distribution

[0271] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology comprise an increased distribution relative to a control. The increased distribution may be an increase in distribution of the non-naturally occurring melanocortin analogs at a given time point relative to a control administered at the same dose and measured at the same time point. The distribution may be measured at an intermediate time point or a final time point.

[0272] In some embodiments, the measurement of distribution comprises measuring a volume of distribution at the terminal phase (Vd or Vdi3), a central volume of distribution (V), a peripheral volume of distribution (V2), an apparent volume of distribution (Vz), or a measurement of distribution comprises measuring a volume of distribution at steady state (Vss). A high or increased Vd, V c, Vz, and / or Vssmay suggest large distribution beyond the tissue, plasma, and / or serum compartment, relative to the control.

[0273] In some embodiments, the increase in distribution comprises a measurement 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 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0274] In some embodiments, the increase in distribution comprises a measurement 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 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0275] In some embodiments, the increase in distribution comprises a measurement 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 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0276] In some embodiments, the increase in distribution comprises a measurement during administration of the non-naturally occurring melanocortin analogs.

[0277] In some embodiments, the increase in distribution comprises a measurement at the completion of administration of the non-naturally occurring melanocortin analogs.Additional pD and pK Embodiments

[0278] In some embodiments, the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following:(a) an increase in half-life relative to a control;(b) a reduction in clearance relative to a control;(c) an increase in tissue concentration relative to a control;(d) an increase in plasma concentration relative to a control;(e) an increase in serum concentration relative to a control;(f) an increase in distribution relative to a control;(g) an increase in an AUC measurement relative to a control;(h) an increase in a DNAUC measurement relative to a control;(i) an increase in Ttmai relative to a control;(j) an increase in Cmax relative to a control;(k) an increase in Cmin relative to a control;(l) an increase in DNCmin relative to a control;(m) an increase in MRT relative to a control;(n) an increase in Cavg relative to a control;(o) an increase in Ctrough relative to a control;(p) an increase in CT relative to a control;(q) an increase in Vd relative to a control;(r) a reduction in Tmax relative to a control; or(s) a reduction in Q relative to a control.

[0279] In some embodiments, the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following, relative to a control:(a) an increase in half-life 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% relative to a control;(b) a reduction in clearance by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control;(c) an increase in tissue concentration 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% relative to a control;(d) an increase in plasma concentration 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% relative to a control;(e) an increase in serum concentration 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% relative to a control;(f) an increase in distribution 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% relative to a control;(g) an increase in an AUG 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% measurement relative to a control;(h) an increase in a DNAUC measurement 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% relative to a control;(i) an increase in Ttinai 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% relative to a control;(j) an increase in Cmax 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% relative to a control;(k) an increase in Cmin 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% relative to a control;(l) an increase in DNCmin 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% relative to a control;(m) an increase in MRT 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% relative to a control;(n) an increase in Cavg 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% relative to a control;(o) an increase in Ctrough 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% relative to a control;(p) an increase in CT 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% relative to a control;(q) an increase in Vd 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% relative to a control;(r) a reduction in Tmax by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control; or(s) a reduction in Q by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control.EXAMPLES

[0280] The following examples are intended to illustrate various embodiments of the present technology. As such, the specific embodiments discussed are not to be construed as limitations on the scope of the present technology. It will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of present technology, and it is understood that such equivalent embodiments, are to be included herein. Further, all references cited herein are hereby incorporated by reference in their entirety, as if fully set forth herein.Example 1: Peptide Synthesis-Generic

[0281] The non-naturally occurring melanocortin analogs of the present technology were synthesized by conventional procedures (e.g., solution-phase procedure, solid-phase synthesis) for the formation of a peptide linkage between amino acids. The solution-phase procedure involved a condensation between the free alpha amino group of an amino acid or derivative thereof having the carboxyl group or other reactive groups protected and the free primary carboxyl group of another amino acid or derivative thereof having the amino group or other reactive groups protected. The solidphase synthesis utilized a variety of resins and reagents and may involve additional purification steps.

[0282] The process for synthesizing the non-naturally occurring melanocortin analogs was generally performed by a procedure as follows. Each amino acid in the desired sequence of the non-naturally occurring melanocortin analogs was added one at a time in succession to another amino acid or derivative thereof or by a procedure whereby peptide fragments with the desired amino acid sequence were first synthesized conventionally and then condensed to provide the desired peptide. In most cases, the resulting peptide was then cyclized to yield a cyclic peptide.

[0283] Solid-phase peptide synthesis was carried out by sequentially incorporating the desired amino acid residues one at a time into the growing peptide chain coupled to a solid-phase support according to the general principles of solid phase methods (see 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)). An exemplary solid-phase synthesis of non-naturally occurring melanocortin analogs is provided below.

[0284] Initially, the C-terminal amino acid residue of the non-naturally occurring melanocortin analog was coupled to a solid-phase support, e.g., a solid-phase resin. Coupling of the C-terminal amino acid residue and the solid-phase support may be carried out according to any method know in the art. Depending on the coupling method, the alpha-amine of the C-terminal amino acid residue may or may not be protected with an amine protecting group, as described below. Likewise, the carboxyl group of the amino acid residue may or may not be activated prior to coupling to the solid-phase support in order to increase its electrophilicity. Some methods of coupling rely on theformation of an ester bond between the carboxyl group of the amino acid and a reactive handle on the solid-phase resin. For example, an amino acid residue may be coupled to a p-benzyloxybenzyl alcohol resin (Wang) or a 2-ch lorotrityl chloride resin via an ester linkage. Some methods of coupling rely on the formation of an amide bond between the carboxyl group of the amino acid and a reactive handle on the solid-phase resin For example, an amino acid residue may be coupled to a benzhydrylamine (BHA) resin through an Fmoc-linker such as, for example, p-[(R,S)-a-[1 -(9H-fluor-en-9-yl)- methoxyformamido]-2,4-dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) via an amide linkage.

[0285] The non-naturally occurring melanocortin analog was then synthesized by sequential amino acid addition or combination of peptide fragments. Subsequently, the peptide was cleaved from the solid-phase support and purified by methods known in the art, such as, for example, reverse phase high performance liquid chromatography (RP-HPLC) using a suitable column, such as a C18 column. Additionally, or alternatively, other methods of separation or purification were employed, including, but not limited to, methods based on the size or charge of the peptide. Once purified, the peptide was characterized by methods such as high-performance liquid chromatograph (HPLC), amino acid analysis, mass spectrometry, and the like.Example 2: Peptide Synthesis-Protecting Groups

[0286] During synthesis of the non-naturally occurring melanocortin analogs, reactive side chain groups of the various amino acid residues were protected with suitable protecting groups, which prevented undesirable chemical reaction from occurring at that site until the protecting group was removed.

[0287] Additionally, protection of the alpha amino group of an amino acid residue or fragment was performed while that entity reacting with the carboxyl group, followed by the selective removal of the alpha amino protecting group to allow a subsequent reaction to take place at that site. Specific protecting groups for solid phase synthesis methods and solution phase synthesis methods are known to those having ordinary skill in the art. Alpha amino groups were protected by a suitable protecting group, including a urethane-type protecting group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, p-biphenyl-isopropoxycarbonyl, 9-fluorenylmethoxycarbonyl(Fmoc) and p-methoxybenzyloxycarbonyl (Moz); aliphatic urethane-type protecting groups, such as t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc was also used for alpha amino protection. Guanidino groups, if present, were protected by a suitable protecting group, such as nitro, p-toluenesulfonyl (Tos), Z, pentamethylchromanesulfonyl (Pmc), adamantyloxycarbonyl, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and Boc. Pmc was used as a protecting group for Arg.

[0288] Alpha aminoprotecting groups may be removed under basic conditions, such as, for example, using a solution of piperidine, piperazine, diethylamine, or morpholine (20-40% v / v) in N,N-dimethylformamide (DMF). In synthesis methods in which alpha amino protecting groups were used, protecting groups were removed after synthesis of the peptide and before or after cleavage of the solid-phase support.Example 3: Peptide Synthesis-Additional Modifications

[0289] If necessary, the peptides were further modified to obtain N-terminus modifications, such as acetylation, while on resin, or were removed from the resin by use of a cleaving reagent and then modified. Likewise, C-terminus modification (e.g., amidation), was performed if needed.

[0290] Additionally, the cyclized peptide structures were obtained prior to cleavage from the peptide resin. For cyclization through reactive side chain moieties, the desired side chains were deprotected, and the peptide suspended in a suitable solvent and a cyclic coupling agent added. Suitable solvents, for example DMF, dichloromethane (DCM) or 1 -methyl-2-pyrrolidone (NMP), were used for the cyclization. Suitable cyclic coupling reagents (e.g., 2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1-yl-oxy- tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1 -yl-oxy- tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2-(7-aza-1 H-benzotriazol- 1 -yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1 (2H)-pyridyl)- 1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TPTU), N,N'-dicyclohexylcarbodiimide / 1- hydroxybenzotriazole (DCCI / HOBt)) were also used for the cyclization. Coupling was initiated by a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N-methylmorpholine (NMM).Example 4: Biological Data

[0291] The agonist and antagonist activity of exemplary non-naturally occurring melanocortin analogs at the melanocortin receptors (e.g., MC1 R, MC3R, MC4R, and MC5R) were measured via cAMP accumulation assay, according to the following procedure. Experimental design and execution were conducted by Epics Therapeutics S.A. EuroscreenFast (Bruxelles, Belgium).Compound Handing

[0292] Compounds were delivered as powder (1 mg) or 10 mM solutions (100 pl) in 100% DMSO. Powders were solubilized in 100% DMSO at a concentration of 10 mM (master solution) in a solvent volume defined. Serial dilutions were performed from master solution in 100% DMSO to obtain intermediate concentrations 200-, 300- or 400- fold higher than the concentrations to be tested, depending on the assay. Each sample was diluted 100-fold in the assay buffer and dispensed in a test plate. Amounts, solvents, and dilutions were estimated based on standard small-molecule drugs. Cell lines used for functional assays are shown in Table 1 .Table 1. Cell linesCompound Testing

[0293] Compounds were tested for (i) agonist and / or antagonist activity at the human MC3 (FAST-0232C) and MC4 (FAST-0233C) receptors, (ii) agonist activity at the human MC1 (FAST-0230C) receptor, and / or (iii) agonist activity at the human MC5 (FAST-0233C) receptor at the following nanomolar concentrations, in duplicate: 0.0001 , 0.001 , 0.01 , 0.03, 0.1 , 0.3, 1 , 10, 100, and 1 ,000.Testing Protocol

[0294] Cyclic AMP (cAMP) Homogenous Time-Resolved Fluorescence (HTRF) assay for Gs coupled receptor:

[0295] CHO-K1 cells expressing recombinant human receptor grown prior to the test in media without antibiotic were detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in assay buffer (KRH: 5 mM KOI, 1 .25 mM MgSO4, 124 mM NaCI, 25 mM HEPES, 13.3 mM Glucose, 1 .25 mM KH2PO4, 1.45 mM CaCI2, 0.5 g / l BSA, supplemented with I mM IBMX or 25pM Rolipram).

[0296] Dose response curves were performed in parallel with the reference compounds.

[0297] For agonist test (384well): 5 pl of cells were mixed with 5 pl of the test compound at increasing concentrations and then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated 1 -hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit.

[0298] For antagonist test (384well): 5 pl of cells were mixed in the wells of an assay plate with 5 pl of a mix of test compound at increasing concentrations and reference agonist for a final concentration corresponding to the historical EC80. The plates were then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated 1 -hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit.Quality Control for Compound Testing

[0299] On each day of experimentation and prior to the testing of compounds, reference compounds were tested at several concentrations in duplicate (n=2) to obtain a dose-response curve and an estimated EC50 and / or IC50 values.

[0300] Reference values thus obtained for the test were compared to historical values obtained from the same receptor and used to validate the experimental session.

[0301] A session was considered as valid only if the reference value was found to be within a 0.5 logs interval from the historical value.

[0302] For replicate determinations, the maximum variability tolerated in the test was of + / -20% around the average of the replicates.Non-naturally Occurring Melanocortin Analog Grouping

[0303] Group A included non-naturally occurring melanocortin analogs A1 to A3, all of which are cyclic peptides comprising the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) or Pro-Phe-Arg-Trp (SEQ ID NO: 358) and cyclized through a lactam bond between Asp and Lys. Group A non-naturally occurring melanocortin analogs are provided in Table 2.Table 2. Group A non-naturally occurring melanocortin analogs

[0304] Group B included non-naturally occurring melanocortin analogs B1 to B4, all of which are cyclic peptides comprising the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) and cyclized through a lactam bond between Asp and Lys. Group B melanocortin analogs include an N-terminal extension. Group B non-naturally occurring melanocortin analogs are provided in Table 3.Table 3. Group B non-naturally occurring melanocortin analogs

[0305] Group C included non-naturally occurring melanocortin analogs C1 to C34, all of which are cyclic peptides comprising the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) and cyclized through a lactam bond between Asp and Lys. Group C melanocortin analogs include an N-terminal amino acid other than Nle. Group C non-naturally occurring melanocortin analogs are provided in Table 4.Table 4. Group C non-naturally occurring melanocortin analogs

[0306] Group D included non-naturally occurring melanocortin analogs D1 to D23, all of which are cyclic peptides comprising a derivative of the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) and cyclized through a lactam bond between Asp and Lys. Derivatives of the motif of SEQ ID NO: 353 included in Group D melanocortin analogs include substitution of Pro for another amino acid. Group D non-naturally occurring melanocortin analogs are provided in Table 5.Table 5. Group D non-naturally occurring melanocortin analogs

[0307] Group E included non-naturally occurring melanocortin analogs E1 to E9, all of which are cyclic peptides comprising a derivative of the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) and cyclized through a lactam bond between Asp and Lys. Derivatives of the motif of SEQ ID NO: 353 included in Group E melanocortin analogs include substitution of Arg for another amino acid or substitution of Trp for another amino acid. Group E non-naturally occurring melanocortin analogs are provided in Table 6.Table 6. Group E non-naturally occurring melanocortin analogs

[0308] Group F included non-naturally occurring melanocortin analogs F1 to F57, all of which are cyclic peptides comprising the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) and cyclized through a lactam bond between Asp and Lys. Group F melanocortin analogs include a C-terminal extension other than dVal-dPro. Group F non-naturally occurring melanocortin analogs are provided in Table 7.Table 7. Group F non-naturally occurring melanocortin analogs

[0309] Group G included non-naturally occurring melanocortin analogs G1 to G4, all of which are cyclic peptides comprising a derivative of the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) and cyclized through a lactam bond between Asp and Lys. Group G melanocortin analog include a Pro or Gly after the Trp residue. Group G non-naturally occurring melanocortin analogs are provided in Table 8.Table 8. Group G non-naturally occurring melanocortin analogs

[0310] Group H included non-naturally occurring melanocortin analogs H1 to H5, all of which are cyclic peptides comprising a derivative of the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) and cyclized through a disulfide bond. Group H non-naturally occurring melanocortin analogs are provided in Table 9.Table 9. Group H non-naturally occurring melanocortin analogs

[0311] Group I included non-naturally occurring melanocortin analogs 11 to 131 , all of which are cyclic peptides comprising a derivative of the motif Trp-Pro-dPhe-Arg-Trp (SEQ ID NO: 354) or a derivative thereof. Derivatives of the motif of SEQ ID NO: 354 may include substitution of Trp for another amino acid or substitution of Pro for another amino acid. Group I non-naturally occurring melanocortin analogs are provided in Table 10.Table 10. Group D non-naturally occurring melanocortin analogs

[0312] Group J included non-naturally occurring melanocortin analogs J1 to J3, all of which are cyclic peptides comprising a derivative of the motif Ala-His-dPhe-Arg-Trp (SEQ ID NO: 355) or a derivative thereof. Derivatives of the motif of SEQ ID NO: 355may include substitution of Ala for another amino acid, for example dAla. Group J non- naturally occurring melanocortin analogs are provided in Table 11 .Table 11. Group J non-naturally occurring melanocortin analogs

[0313] Group K included non-naturally occurring melanocortin analogs K1 to K4, all of which are cyclic peptides comprising a derivative of the motif Phe-His-dPhe-Arg- Trp (SEQ ID NO: 356). Group K non-naturally occurring melanocortin analogs are provided in Table 12.Table 12. Group K non-naturally occurring melanocortin analogs

[0314] Group L included non-naturally occurring melanocortin analogs L1 to L22, all of which are cyclic peptides comprising a derivative of the motif His-p(CI)dPhe-Arg- Trp (SEQ ID NO: 357), or a derivative thereof. Derivatives of the motif of SEQ ID NO: 357 may include substitutions of His for another amino acid, for example, Aba, Aia, and Ata, or substitutions of p(CI)dPhe for another amino acid, for example, p(Br)dPhe. Group L non-naturally occurring melanocortin analogs are provided in Table 13.Table 13. Group L non-naturally occurring melanocortin analogs

[0315] Group M included non-naturally occurring melanocortin analogs M1 to M31 , all of which are cyclic peptides comprising a derivative of the motif Pro-p(F)dPhe-Arg- Trp (SEQ ID NO: 359), or a derivative thereof. Derivatives of the motif of SEQ ID NO: 359 may include substitutions of Pro for another amino acid, for example, His, dGIn, and dTyr, or substitutions of Trp for another amino acid, for example, dNal(2’). Group M non-naturally occurring melanocortin analogs are provided in Table 14.Table 14. Group M non-naturally occurring melanocortin analogs

[0316] Group O included non-naturally occurring melanocortin analogs 01 , 02, 07, 01 1 , all of which are cyclic peptides comprising the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) or Pro-p(F)dPhe-Arg-Trp (SEQ ID NO: 359), and are cyclized through a lactam bond between Asp or Glu and Orn. Group O non-naturally occurring melanocortin analogs are provided in Table 15.Table 15. Group O non-naturally occurring melanocortin analogsAgonist activity of melanocortin analogs on melanocortin 1 and 5 receptors

[0317] Administration of some non-naturally occurring melanocortin analogs activated melanocortin 1 receptor (MC1 R) and / or melanocortin 5 receptor (MC5R) activity, as measured by cAMP levels (Table 16).Table 16. Dose-response results of melanocortin analogs and control against the melanocortin 1 receptor (MC1 R) and melanocortin 5 receptor (MC5R)Agonist activity of melanocortin analogs on melanocortin 3 and 4 receptors

[0318] Administration of some non-naturally occurring melanocortin analogs activated melanocortin 3 receptor (MC3R) activity and / or melanocortin 4 receptor (MC4R) activity, as measured by cAMP levels (Table 17).Table 17. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R)n.c. = not calculatedAntagonist activity of melanocortin analogs on melanocortin 3 or 4 receptor

[0319] Administration of some non-naturally occurring melanocortin analogs inhibited melanocortin 3 receptor (MC3R) and / or melanocortin 4 receptor (MC4R) activity, as measured by cAMP levels (Table 18).Table 18. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R)n.c. = not calculatedComparison of agonist and antagonist activity of 07 and 011 to similar melanocortin analogs

[0320] To determine the impact that certain features of the melanocortin analogs of the present technology had on agonist activity at the different melanocortin receptors, the agonist and antagonist activity of 07 and 01 1 was compared to the agonist and antagonist activity of similar sequences. Specifically, 07 and 01 1 were compared to sequences with different lactam cyclization types, different residues at the R4and R3positions, and different C-terminal residues. The agonist and antagonist activity of 07 and comparative sequences is provided in Table 19 and Table 20 and the agonist and antagonist activity of 01 1 and comparative sequences is provided in Table 21 and 22.Table 19. Agonist activity of 07 and melanocortin analogs with point mutations relative to 07Table 20. Antagonist activity of 07 and melanocortin analogs with point mutations relative to 07Table 21. Agonist activity of 011 and melanocortin analogs with point mutations relative to 011Table 22. Antagonist activity of 011 and melanocortin analogs with point mutations relative to 011

[0321] As shown in Tables 19-22, all else equal, the Glu / Orn cyclization of 07 and 01 1 clearly impacts the agonism on MC3R, however, the cyclization does not appear to have the same impact on agonism of MC4R and antagonism of MC3R and MC4R. Even more stark is the difference in agonism / antagonism of MC3R and MC4R observed when p(F)dPhe or dPhe is substituted for a larger residue, such as p(Br)dPhe or p(l)dPhe. For example, SEO ID NOs: 216 and 218, which have smaller p(F)dPhe and dPhe at the R4position, are full agonists on MC4R, whereas SEQ ID NOs: 249 and 364, which have larger p(Br)dPhe and p(l)dPhe at the R4position, are full antagonists on MC4R. Additionally, a substantial change in agonist activity on the MC3 receptor was observed when His was substituted for Pro at position R3in the melanocortin analogs. Specifically, SEQ ID NOs: 216 and 218, which have Pro at R3, exhibited moderate binding and partial agonism on MC3R, whereas SEQ ID NOs: 326 and 363, which have His at R3, exhibited strong binding and full agonism on MC3R.Residual binding of melanocortin analogs on melanocortin 1 receptor

[0322] The residual binding of some of the non-naturally occurring melanocortin analogs was measured on the melanocortin 1 receptor (MC1 R) by RLB assay (Table23).Table 23. Dose-response binding results of melanocortin analogs and control against the melanocortin 1 receptor (MC1 R)Residual binding of melanocortin analogs on melanocortin 3 receptor

[0323] The residual binding of some of the non-naturally occurring melanocortin analogs was measured on the melanocortin 3 receptor (MC3R) by RLB assay (Table24).Table 24. Dose-response binding results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R)Residual binding of melanocortin analogs on melanocortin 4 receptor

[0324] The residual binding of some of the non-naturally occurring melanocortin analogs was measured on the melanocortin 4 receptor (MC4R) by RLB assay (Table25).Table 25. Dose-response binding results of melanocortin analogs and control against the melanocortin 4 receptor (MC4R)Residual binding of melanocortin analogs on melanocortin 5 receptor

[0325] The residual binding of some of the non-naturally occurring melanocortin analogs was measured on the melanocortin 5 receptor (MC5R) by RLB assay (Table 26).Table 26. Dose-response binding results of melanocortin analogs and control against the melanocortin 5 receptor (MC5R)Agonist activity on GPR54

[0326] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on GPR54 by Aequorin assay. Results from this assay are provided in Table 27.Table 27. Dose-response results of melanocortin analogs and control against GPR54Antagonist activity on GPR54

[0327] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on GPR54 by Aequorin assay. Results from this assay are provided in Table 28.Table 28. Dose-response results of melanocortin analogs and control against GPR54Agonist activity on QRFP

[0328] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on QRFP by Aequorin assay. Results from this assay are provided in Table 29.Table 29. Dose-response results of melanocortin analogs and control against QRFPAntagonist activity on QRFP

[0329] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on QRFP by Aequorin assay. Results from this assay are provided in Table 30.Table 30. Dose-response results of melanocortin analogs and control against QRFPAgonist activity on PrRP

[0330] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on PrRP by Aequorin assay. Results from this assay are provided in Table 31 .Table 31. Dose-response results of melanocortin analogs and control against PrRPAntagonist activity on PrRP

[0331] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on PrRP by Aequorin assay. Results from this assay are provided in Table 32.Table 32. Dose-response results of melanocortin analogs and control against PrRPAgonist activity on NPFF2S

[0332] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPFF2S by Aequorin assay. Results from this assay are provided in Table 33.Table 33. Dose-response results of melanocortin analogs and control against NPFF2SAntagonist activity on NPFF2S

[0333] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPFF2S by Aequorin assay. Results from this assay are provided in Table 34.Table 34. Dose-response results of melanocortin analogs and control against NPFF2SAgonist activity on NPY1

[0334] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPY1 by cAMP assay. Results from this assay are provided in Table 35.Table 35. Dose-response results of melanocortin analogs and control against NPY1Antagonist activity on NPY 1

[0335] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPY1 by cAMP assay. Results from this assay are provided in Table 36.Table 36. Dose-response results of melanocortin analogs and control against NPY1Agonist activity on NPFF1

[0336] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPFF1 by cAMP assay. Results from this assay are provided in Table 37.Table 37. Dose-response results of melanocortin analogs and control against NPFF1Antagonist activity on NPFF1

[0337] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPFF1 by cAMP assay. Results from this assay are provided in Table 38.Table 38. Dose-response results of melanocortin analogs and control against NPFF1Example 5: Pharmacokinetic Assessment of Non-Naturallv Occurring Melanocortin Analogs Following Oral Administration to Rats and Cynomolgus MonkeysStudy Objective

[0338] The objective of this study is to determine the pharmacokinetics of non- naturally occurring melanocortin analogs of the present technology following oral gavage administration in male rats and single oral administration to non-naive male cynomolgus monkeys. In rats, the test article will be monitored in plasma for up to 24 hours post each dose. Study design and sample collection will be conducted as outlined in Table 39 and Table 40.Table 39. Study DesignTable 40. Sample CollectionsE: Anticoagulant: Potassium (K2) EDTA;P: plasmaC: cerebrospinal fluid‘Sampled only for certain compounds

[0339] Dose Solution Analysis Samples: After each dose preparation, remove approximately 0.5 mL aliquots from the formulations, transfer the aliquots into amber HPLC vials and stored at -60°C or lower until assayed in duplicate for dose validation.

[0340] Disposition of Remaining Test Article Formulations: Remaining formulations will be stored at -60°C or lower.

[0341] Disposition of Remaining Test Article (dry powder or solid): Remaining test article will be stored at room temperature desiccated, and protected from light until shipment or discard.

[0342] Animals will be fasted overnight through 4 hours post dosing.Vehicle and Formulation Preparation:

[0343] Appropriate amount of test article will be accurately weighed and mixed with appropriate volume of vehicle to get a clear solution or suspension.

[0344] Formulation samples will be removed from each of the formulation solutions, transferred into 1 .5 mL of polypropylene microcentrifuge tubes and run dose validation by LC / UV or LC-MS / MS.

[0345] Compounds to be assessed are outlined in Table 41 .Table 41 . CompoundsCF: FW / MW / purityAnimal Specifications: Cynomolgus Monkeys

[0346] Cynomolgus Monkey specifications are outlined in Table 42.Table 42. Cynomolgus Monkey Specifications

[0347] Environmental Conditions: Environment controls will be set to maintain a temperature range of 20-26°C, a relative humidity range of 40 to 70%, and a 12-hour light / 12-hour dark cycle. The light / dark cycle may be interrupted for study-related activities.

[0348] Housing: Animals will be group-housed (up to four animals / sex / cage) in polysulfone cages with certified aspen shaving bedding or corncob bedding during acclimation and study period. While animals may be individually housed after surgery or when there is special requirement in protocol, as well as, for behavioral or health reasons or due to cage mate death.

[0349] Diet and Feeding: Animals were offered certified rodent breeding and growth diet ad libitum every day, unless fasted for study procedures. Each lot of the diet is analyzed for nutrients, chemical contaminant and microorganisms, the results are reviewed and evaluated by veterinarians before provided to animals.

[0350] Drinking Water: Autoclaved RO (reverses osmosis) water will be available to all animals, ad libum.

[0351] Feed and Water Analyses: Autoclaved RO water will be provided ad libitum via water bottle. Water samples are periodically analyzed by a certified laboratory for specified microorganisms and environment contaminants. The diet is routinely analyzed by the manufacturer for specified microorganisms, nutritional components and environmental contaminants.

[0352] Environmental Enrichment: Enrichment toys will be provided.

[0353] Dose Administration: The dose volume will be determined by the animals' body weight collected on the morning of dosing day.Animal Specifications: Rats

[0354] Rat specifications are outlined in Table 43.Table 43. Rat SpecificationsObservations and Examinations

[0355] Clinical Observations: All animals will be observed at dosing and each scheduled collection. All abnormalities will be recorded.

[0356] Body Weight: All animals will be weighed on the dosing day prior to dosing to determine the dose volume to be administered.Sample Collection and Processing

[0357] Blood Sample Collection and Process: At least 0.1 mL blood will be collected at each time point. All blood samples will be collected via jugular vein. All blood samples will be transferred into low binding EP tube with anticoagulant (0.5 M Potassium (K2) EDTA will be pre-added as a ratio of 50:1 for blood: anticoagulant), 0.05% Triton X-100 (e.g., 100uL Blood+2uL 2.5% Triton X-100) will be used for desorption the blood samples will be placed on wet ice.

[0358] Blood samples will be centrifuged within 1 hr of collection at 3,200 g 4°C for 10 minutes. Following centrifugation, plasma samples will be transferred into their respective pre-labeled low binding EP tube and immediately frozen over dry ice. The plasma samples will be stored lower than -60°C until bioanalysis.

[0359] LC-MS / MS method development:

[0360] A LC-MS / MS method for the quantitative determination of test compound in biological matrix will be developed.

[0361] N in 1 cassette LC-MS / MS method may be developed for samples coming from different studies as long as these studies belong to the same sponsor.

[0362] Cassette administration assay could be performed if the mass difference (AMass) among different analytes is >4 Da. In this case, interference evaluation is not necessary.

[0363] If AMass among different analytes is less than 4 Da, there is a potential risk that interference would occur during LC-MS / MS analysis. If such kind of cassette assayis still requested by client, interference among analytes will not be evaluated but the LC separation of those analytes by using a generic method will be attempted.

[0364] Sample analysis:

[0365] A calibration curve with at least 6 non-zero calibration standards will be applied for each batch including LLOQ.

[0366] If sample number within a batch is < 12, at least one set of standard curve separated with two parts through begin and end of the sequence should be included in the run and QCs are not required. The recommended injection order is C8, C6, C4, C2, study samples, C7, C5, C3, C1 .

[0367] If sample number within a batch is > 12, one standard curve and two sets of QCs with low, middle and high concentrations will be applied for bioanalysis. Meanwhile, QCs number should be more than 5% of study sample number.

[0368] Samples, coming from one client with the same type of matrix in different studies, are allowed to be quantified in one analysis run by using the developed N in 1 cassette LC-MS / MS method.

[0369] Acceptance criteria:

[0370] (1 ) Linearity: At least 75% of the calibration standards should fall within±20% of their nominal values for biofluid and within ±25% of their nominal values for tissue and feces samples. If the endpoints, such as LLOQ and ULOQ, on the calibration curve are eliminated, the calibration curve will be truncated. The truncated calibration curve should consist of at least 75% of the initial STDs.

[0371] (2) Accuracy: At least 67% of QCs should fall within ±20% of their nominal values for biofluid and within ±25% of their nominal values for tissue and feces samples. At least half of QCs at each concentration should be passed.

[0372] (3) Specificity: The mass response of analyte in the double blank and blank should be < 50% LLOQ.

[0373] (4) Sensitivity: The LLOQ will be tried to target < 3 ng / mL. Any adjustment of LLOQ will be informed to client in advance.

[0374] (5) Carryover: The mean calculated carryover peak area in the double blanks or blanks immediately after the highest standard injection should be less thanthat of LLOQ. If the carryover couldn’t meet the criteria, the impact of the carryover on unknown samples should be re-evaluated according to the below procedure:

[0375] Carryover should be re-evaluated based on absolute carryover. Absolute carryover is calculated by carryover contribution multiplies carryover impact, where the carryover contribution is calculated by the area ratio of the double blank or blank with the highest carryover (Area max of carryover blank) to the ULOQ with the minimum calculated value (Area min of ULOQ), and the carryover impact is calculated by the area ratio of one injection (Area of one injection) to the following injection (Area of the following injection). The absolute carryover should be below the acceptable accuracy of the studies (e.g., 20% or 25%).

[0376] Carryover contribution = Areamax of carryover blank I Areamin of ULOQ Carryover impact = Area of one injection / Area of the following injection Absolute carryover = Carryover contribution * Carryover impactData Analysis

[0377] Plasma concentration versus time data for Compounds A-C in Rats and Cynomolgus Monkeys will be plotted in graph and analyzed by non-compartmental approaches. Related PK parameters will be calculated according to dosing route, e.g., Cl, Vdss and CO for intravenous administration, Cmax, Tmax or %F for extravascular administration, and T1 / ?, AUC(o-t), AUC<o-inf), MRT(o-t), MRT(o-inf) for all routes. Preliminary plasma results after 24 hours for 60 mg / kg oral administration in Rats and 30mg / kg of Compounds A-C in Cynomolgus Monkeys are shown in Table 44 and FIG. 1 .Table 44. Plasma Pharmacokinetic Results of Compounds A-C after 24 hours

[0378] Plasma concentration versus time data for Compound D (07) (FIGS. 2A- 2C) in Cynomolgus Monkeys was plotted in graphs and analyzed by non-compartmentalapproaches. Related PK parameters were calculated according to dosing route, e.g., Cl, Vdss and CO for intravenous administration, Cmax, Tmax or %F for extravascular administration, and T1 / 2, AUC(o-t), AUC(o-inf), MRT(o-t), MRT(o-inf) for all routes. Preliminary plasma results after 24 hours of 3 mg / kg, 10 mg / kg, 30 mg / kg, or 60 mg / kg PO administration of Compound D (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2; 07) in Cynomolgus Monkeys are shown in Table 45.Table 45. Plasma Pharmacokinetic Results of Compound (07) in Cynomolgus Monkeys after 24 hours

[0379] Preliminary plasma and cerebrospinal fluid (CSF) results after 24 hours of administration of Compound D (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2; 07) and Compound F (Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2) in Rats are shown in Table 46 and Table 47. Graphs of plasma concentration and CSF concentration in Rats are shown in FIGS 3A-3D (SC administration), FIGS. 4A-4D (IP administration), and FIGS. 5A-5C (PO administration).

[0380] Plasma and CSF concentrations over 24 hours after administration of Compound D (07) or setmelanotide were also assessed (FIGS. 4H-4K). It was predictedTable 46. Plasma Pharmacokinetic Results of Compound D (07) in Rats after 24 hoursTable 47. CSF Pharmacokinetic Results of Compound D (07) in Rats after 24 hoursND = Not determined

[0381] Dose proportionality of Compound D (07) following a single administration via SC, IP, and PO in Rats is shown in Tables 48-50.Table 48. Dose Proportionality of Compounds D and E in Rats after a single SC administrationTable 49. Dose Proportionality of Compound D in Rats after a single IP administrationTable 50. Dose Proportionality of Compound D in Rats after a single PO administration

[0382] Preliminary plasma and cerebrospinal fluid (CSF) results after 24 hours of SC and IP administration of Compound F (Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal- dPro-NH2) in Rats are shown in Table 51 and Table 52. Graphs of plasma concentrationand CSF concentration in Rats are shown in FIGS 6A-6D (SC administration) and 7A- 70 (IP administration).Table 51 . Concentration of Compound F in plasma and CSF of Rats over timeND = not determinedTable 52. Plasma Pharmacokinetic Results of Compound F in Rats after 24 hours

[0383] Dose proportionality of Compound F in male rats following a single SC or IP administration in Rats is shown in Table 53 and Table 54 and FIG 8.Table 53. Dose Proportionality of Compound F in Rats after a single SC administrationTable 54. Dose Proportionality of Compound F in Rats after a single IP administration

[0384] Preliminary plasma and cerebrospinal fluid (CSF) results after 1 .5 hours of IV bolus administration of 1 .0 mg / kg of Compound F in Rats are shown in Table 55 and Table 56.Table 55. Concentration of Compound F in plasma and CSF of Rats over timeTable 56. Plasma and CSF Pharmacokinetic Results of Compound F in Rats after IV bolus administrationND = Not determined

[0385] FIG. 9 illustrates the average plasma concentration of Compound F over time in rats following SC, IP, and IV bolus administration.Plasma Concentration

[0386] Plasma pharmacokinetic measurements using 30 mg / kg were assessed in Cynomolgus monkey plasma up to 24 hours. Results are detailed in Table 57.Table 57: Pharmacokinetic Data

[0387] The antagonist activity of exemplary non-naturally occurring melanocortin analogs at specific ion channels was measured using the Qube electrophysiological platform. The non-naturally occurring melanocortin analogs and specific ion channel targets are provided in Table 58.Table 58. Ion channel targets and melanocortin analogsMethods

[0388] The non-naturally occurring melanocortin analogs identified above were tested for antagonist activity at various ion channels at concentrations ranging from 0.1 mM to 30 mM. In each experiment and if applicable, the respective reference compounds were tested concurrently with the test compounds, and the data were compared with known historical values. hNayl .5 Sodium Channel Assay - Qube APC

[0389] Onset and steady state block of peak Navi .5 current is measured using a pulse pattern, repeated every 5 sec, consisting of a hyperpolarizing pulse to -120mV for a 200ms duration, depolarization to -15mV amplitude for a 40ms duration, followed by step to 40mV for 200ms and finally a 100ms ramp (1 .2 V / s) to a holding potential of - 80mV. Peak current is measured during the step to -15mV.

[0390] The parameters measured were difference between the peak inward current on stepping to -15mV (i.e., peak of the current) and the leak current. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control is the mean Nav1.5 current amplitude collected 10 seconds at the end of the vehicle control; Test Compound is the mean Nav1.5 current amplitude collected 10 seconds at the end of test concentration application for each concentration. hKv4.3 / hKChlP2 Potassium Channel Assay - Qube APC

[0391] After whole cell configuration is achieved, the cells are held at -80mV. Onset and steady state block of hKv4.3 current is measured using a pulse pattern from -80mV to 40mV amplitude for a 110ms duration, and finally a 100ms ramp (1.2 V / s) to -80mV. This paradigm is delivered once every 5s to monitor the current amplitude.

[0392] The parameters measured were the maximum outward current evoked on stepping to 40mV from holding potential of -80mV. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control data is the mean Kv4.3 / KChlP2 current amplitude collected 10 seconds at the end of the vehicle control period; Test compound data is the mean Kv4.3 / KChlP2 current amplitude collected 10 seconds at the end of test concentration application for each concentration. hCayl .2 (L-type) CiPA Calcium Channel Assay - Qube APC

[0393] Onset and steady state block of peak hCavl .2 current is measured using a pulse pattern, repeated every 15 sec. Cells were held at -80mV for a 50ms before stepping to -90mV for 100ms to measure leak current and then stepped back to -80mV for 50ms, depolarization to OmV amplitude for a 40ms duration, followed by step to 40mV for 200ms and finally a 100ms ramp (1.2 V / s) to a holding potential of -80 mV. Peak current is measured during the step to OmV. Each concentration is applied for 5 minutes.

[0394] The calcium current amplitude is calculated by measuring the difference between the peak inward current on stepping to OmV or the peak inward current at the ramp (i.e. peak of the current) and the leak current. The calcium current is assessed in vehicle control conditions and at the end of each five (5) minute compound application. hNayl .5 Late Current Sodium Channel Assay - Qube APC

[0395] Onset and steady state block of Late Navi .5 current is measured using a pulse pattern, repeated every 5 sec, consisting of a hyperpolarizing pulse to -120mV for a 200ms duration, depolarization to -15mV amplitude for a 40ms duration, followed by step to 40mV for 200ms and finally a 100ms ramp (1 .2 V / s) to a holding potential of - 80mV. Late current is measured as charge current elicited during the ramp with 50nM ATXIL

[0396] The parameters measured were the ramp current charge (AUG) evoked on ramping back to -80mV from 40mV test pulse in the presence of 50nM ATXII. All data were filtered for seal quality, seal drop, and current. The peak and ramp current amplitude was calculated before and after compound addition and the amount of current was assessed by dividing the Test compound current by the Control current. Control data is the mean hNav1.5 late current collected 15 seconds at the end of 50nM ATXII application (50nM ATXII control); Test compound data is the mean ramp hNav1.5 current collected 15 seconds at the end of test concentration application for each concentration. hERG Potassium Channel Assay - Qube APC

[0397] After whole cell configuration is achieved, the cells are held at -80m V. Cells are held at this voltage for 50ms to measure the leak current, which is subtracted from the tail current on-line. The cells are depolarized to +40mV for 500ms and then to -80 mV over a 100ms ramp to elicit the hERG tail current. This paradigm is delivered once every 8s to monitor the current amplitude. All compounds were tested in the presence of 0.1 % Pluronic F-68 Non-lonic Surfactant and at approximately room temperature.

[0398] The parameters measured were the maximum tail current evoked ramping back to -80mV from the test pulse of 40mV. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control data is the mean hERG current amplitude collected for three pulses (24 seconds) at the end of the vehicle control; Test compound data is the mean hERG current amplitude collected for three pulses (24 seconds) at the end of test concentration application for each concentration. hKCNQ1 / hminK Potassium Channel Assay - Qube APC

[0399] After whole cell configuration is achieved, the cells are held at -80mV. KCNQ1 / minK currents are evoked by a 1000ms pulse from -80m V to 60mV followed by a ramp from 60mV to -80mV over 1 15ms with the outward peak currents measured upon depolarization of the cell membrane. This paradigm is delivered once every 15s to monitor the current amplitude.

[0400] The parameters measured were the maximum outward current evoked on stepping to +60mV from a holding potential of -80mV. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control data is the mean hKCNQ1 / hminK current amplitude collected 30 seconds at the end of vehicle control period; Test compound data is the mean hKCNQ1 / hminK current amplitude collected 30 seconds at the end of test concentration application for each concentration. hKir2.1 Potassium Channel Assay - Qube APC

[0401] After whole cell configuration is achieved, the cells are held at -30mV. Kir2.1 currents are evoked by a single 500ms pulse to -120mV before returning to the holding potential of -30mV. This paradigm is delivered once every 20s to monitor the current amplitude.

[0402] The parameters measured were the maximum inward current elicited on stepping to -120mV for 500ms from a holding potential of -30 mV. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition. Residual non-Kir2.1 current was eliminated via normalization to residual current after application of 100uM Barium Chloride. The amount of Test compound effect was then assessed by dividing the Test compound current amplitude by the Control current amplitude. Control data is the mean Kir2.1 current amplitude collected 40 seconds at the end of the vehicle control; Test compound data is the mean Kir2.1 current amplitude collected 30 seconds at the end of test concentration application for each concentration.Results

[0403] Where presented, IC50 values were determined by a non-linear, least squares regression analysis. Reference standards were run as an integral part of each assay to ensure the validity of the results obtained. Results from the ion channel assessment of non-naturally occurring melanocortin analogs are provided in Table 59.Table 59. Dose-response results of melanocortin analogs and reference compounds against ion channels.*N / C: Indicates observed mean maximal inhibition was <25%Example 7: Assessment of physical biological properties of non-naturallv occurring melanocortin analogs

[0404] Physical biological properties including solubility, in vitro absorption and in vitro metabolism of nine exemplary non-naturally occurring melanocortin analogs were assessed according to the following procedures. In each experiment and if applicable, the respective reference compound was tested concurrently with the test compounds, and the data were compared with known values. Stock solutions of the tested compounds were prepared at a concentration of 0.01 M in DMSO.Solution Properties

[0405] Solution properties of non-naturally occurring melanocortin analogs and reference compounds in various biological media were assessed according to the conditions provided in Table 60.Table 60. Assay conditions for in vitro absorption assessmentAqueous Solubility

[0406] Aqueous solubility (pM) was determined by comparing the peak area of the principal peak in a calibration standard (200 pM) containing organic solvent (methanol / water, 60 / 40, v / v) with the peak area of the corresponding peak in a buffer sample. In addition, chromatographic purity (%) was defined as the peak area of the principal peak relative to the total integrated peak area in the HPLC chromatogram of the calibration standard. A chromatogram of the calibration standard of each test compound, along with a UV / VIS spectrum with labeled absorbance maxima, was generated.

[0407] A chromatogram of the test compound (200 pM) along with a UV / VIS spectrum with labeled absorbance maxima, was generated.Protein Binding

[0408] The peak areas of the test compound in the buffer and test samples were used to calculate percent binding and recovery according to the following formulas:Protein binding(%) = ((AreaP-Areab) / AreaP) x 100Recovery(%) = ((AreaP-Areab) / Areac) x 100 where: AreaP= peak area of analyte in protein matrix; Areab = peak area of analyte in buffer; and Areac= peak area of analyte in control sample.Partition Coefficient

[0409] The total amount of compound was determined as the peak area of the principal peak in a calibration standard (100 pM) containing organic solvent (methanol / water, 60 / 40, v / v). The amount of compound in buffer was determined as the combined, volume-corrected, and weighted areas of the corresponding peaks in the aqueous phases of three organic-aqueous samples of different composition. An automated weighting system was used to ensure the preferred use of raw data from those samples with well quantifiable peak signals. The amount of compound in organic was calculated by subtraction. Subsequently, Log D was calculated as the Log10 of the amount of compound in the organic phase divided by the amount of compound in the aqueous phase.Half-Life Determination

[0410] At the end of the incubation at each of the time points, an equal volume of an organic mixture (acetonitrile / methanol, 50 / 50, v / v) was added to the incubation mixture. Samples were analyzed by HPLC-MS / MS and corresponding peak areas were recorded for each analyte. The ratio of precursor compound remaining after each time point relative to the amount present at time 0, expressed as percent, is reported as chemical stability. The half-life (T1 / 2) was estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) versus time, assuming first order kinetics.

[0411] Results of the solubility assessment detailed above are provided in Tables61 -64.Table 61 . Protein binding of melanocortin analogs in plasmaTable 62. Half-life of melanocortin analogs in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF)Table 63. Aqueous solubility of melanocortin analogs in plasma (PBS), simulated gastric fluid (SGF), and simulated intestinal fluid (SIF)*pH = 7.4Table 64. Partition coefficient of melanocortin analogs and reference compounds*log D, n-octanol / PBS, pH 7.4In Vitro Absorption

[0412] In vitro absorption of non-naturally occurring melanocortin analogs was determined using permeability assays. Assay conditions are provided in Table 65.Table 65. Assay conditions for in vitro absorption assessmentPermeability

[0413] The apparent permeability coefficient (Papp) of the test compound was calculated as follows: Papp(cmZs) = (VR*CR,end / Dt) x (1 / A*(CD,mid-CR,mid) where VR is the volume of the receiver chamber; CR.end is the concentration of the test compound in the receiver chamber at the end time point; At is the incubation time; A is the surface area of the cell monolayer; CD, mid is the calculated mid-point concentration of the test compound in the donor side, which is the mean value of the donor concentration at time 0 minute and the donor concentration at the end time point; and CR.mid is the mid-point concentration of the test compound in the receiver side, which is one half of the receiver concentration at the end time point. Concentrations of the test compound were expressed as peak areas of the test compound.Recovery of the Test Compound from the Permeability Assay

[0414] The recovery of the test compound was calculated as follows:

[0415] ReCOVery(%) = ((VD*CD,end+VR*CR,end) / VD*CD0) x 1 00

[0416] where VD and VR are the volumes of the donor and receiver chambers, respectively; CD, end is the concentration of the test compound in the donor sample at the end time point; CR.end is the concentration of the test compound in the receiver sample at the end time point; and CDO is the concentration of the test compound in the donor sample at time zero. Concentrations of the test compound are expressed as peak areas of the test compound.Fluorescein assessment for Permeability assays

[0417] Fluorescein was used as the cell monolayer integrity marker. Fluorescein permeability assessment (in the A-B direction at pH 7.4 on both sides) was performed after the permeability assay for the test compound. The cell monolayer that had afluorescein permeability of less than 1 .5 x 10-6cm / s for Caco-2 and MDR1 -MDCKII cells and 2.5 x 106cm / s for MDCKII cells was considered intact, and the permeability result of the test compound from intact cell monolayer is reported.

[0418] Results of the in vitro absorption assessments described above are provided in Table 66.Table 66. In vitro absorption of melanocortin analogs and reference compoundsIn Vitro Metabolism

[0419] In vitro metabolism of non-naturally occurring melanocortin analogs was determined using the assay conditions provided in Table 67.Table 67. Assay conditions for in vitro metabolism assessment

[0420] Metabolic stability, expressed as percent of the parent compound remaining, was calculated by comparing the peak area of the compound at the time point relative to that at time-0. The half-life (T1 / 2) was estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) vs. time,assuming the first-order kinetics. The apparent intrinsic clearance (CLint , in pL / min / pmol, pL / min / mg or pL / min / Mcell) was calculated according to the following formula:CLint= 0.693 / (Ti / 2*(mg protein / pL or million cells / pL or pmol CYP isoyme / pL)).

[0421] Results from the intrinsic clearance assay are provided in Table 68.Table 68. In vitro metabolism of melanocortin analogs and reference compoundsExample 8: CYP Inhibition of Non-Naturally Occurring Melanocortin Analogs

[0422] The inhibitory potential of exemplary non-naturally occurring melanocortin analogs was tested on seven human Cytochrome P450 (CYP) enzymes: CYP1 A, CYP2B6, CYP2C19, CYPC8, CYP2C9, CYP2D6, and CYP3A. Exemplary non-naturally occurring melanocortin analog, 07, and comparator non-naturally occurring melanocortin analog Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 368) were tested at concentrations ranging from 0.1 mM to 100 mM for inhibition of the seven CYPs. The CYP inhibition assays were performed using human liver microsomes (HLM) and human recombinant CYP isozymes in 96-well plate format. Direct inhibition (e.g., zero-min incubation) and time-dependent (e.g., 30 min preincubation) inhibition assays were performed. The results of the CYP inhibition assays of 07 at 10 mM are shown in Table 69 and the results of the comparator CYP inhibition assays including ICso values at each of the CYP enzymes are shown in Table 70.Table 69. CYP Inhibition Studies of 07Table 70. GYP Inhibition of B07Example 9: Assessing Weight and Food Intake in an Animal Model

[0423] Weight and food intake were assessed in Sprague-Dawley rats after administration of 3 mg / kg (3mg / kg) A3, 07, and 01 1 for three or four days are shown in FIGS. 10A (weight) and 10B (daily food intake).Example 10: Body Weight, Complete Blood Count, Clinical Chemistry, and Food Intake in an Animal ModelObjective

[0424] The objective of this study was to evaluate the pharmacodynamic (PD) characteristics and effects on food intake, body composition, and clinical chemistry following administration of exemplary non-naturally occurring melanocortin analogs of the present technology. Non-naturally occurring melanocortin analogs were administered to Cynomolgus monkeys via two subcutaneous (s.c.) injections at different doses.Primate Specifications

[0425] Primate specifications are outlined in Table 71 .Table 71 : Primate SpecificationsAnimal Husbandry

[0426] Animals were supplied with unlimited Certified Monkey Diet for 72 hours after dosing on days 1 , 8, and 1 1 . Otherwise, the animals were supplied with Certified Monkey Diet twice a day. Animals received fruit daily as nutritional enrichment.

[0427] Animals were supplied with fresh reverse-osmosis (RO) water using an automated watering system.Study Design

[0428] Non-naturally occurring melanocortin analogs were each administered to a group of Cynomolgus monkeys (n=2 per group) via s.c. injections as outlined in Table72. The start of treatment is designed as Day 1 . The end time of dosing was recorded as Oh.Table 72. Group & Dosing InformationExamination and Observations

[0429] General physical examinations were completed once in the acclimation period. Cage-side observations for general health and appearance, such as nausea and vomiting, were done every hour for 6 hours after dosing on Days 8 and 11. Otherwise, cage-side clinical observations were done once daily during the pre-study and after dosing period.

[0430] Acclimatization Period (Day 1 -7): Each animal was examined at least once during the acclimation period to determine suitability for the study. Body weight, clinical observations, and food intake observations were recorded daily. Measurement of initial body composition using Dual-Energy X-Ray Absorptiometry (DEXA) was recorded at least once during this time. Standard blood markers (e.g., glucose, insulin, HDL-c, LDL- c, triglycerides, total cholesterol, alanine aminotransferase, aspartate aminotransferase) were measured once.

[0431] Treatment Phase (Days 8-49): Body weight was recorded twice a week, clinical observation and food intake were recorded once a day. Standard hematology and clinical chemistry readouts as above were conducted before dosing and at the conclusion of the study on day 49. DEXA measurements of body composition were conducted biweekly.Food intake measurement

[0432] Food intake was observed at about 0.5 hours, 1 hour, 1 .5 hours, 2 hours, 3 hours, 4 hours, 24 hours, 48 hours, and 12. hours after administration of saline or non- naturally occurring melanocortin analogs at 1 mg / kg and 3 mg / kg (Day 8 and Day 11 ) dosing. On Days 4-7, monkeys were acclimatized to a normal diet of two meals per day.On Day 8, the lower dose of the non-naturally occurring melanocortin analogs were administered, and observations continued through Day 10. On Day 11 , the higher dose of the non-naturally occurring melanocortin analogs was administered, and observations continued through Day 13, the conclusion of the study.Blood collection

[0433] Blood collection according to Table 73 was conducted for the following: clinical chemistry (Serum), hematology (whole blood). Whole blood was collected at each time point with syringe via the cephalic or saphenous veins into labeled polypropylene tubes.Table 73. Blood SamplingSample Measurement and Analysis

[0434] Clinical chemistry and hematology assessments were conducted, assessing the parameters outlined in Tables 74 and 75.Table 74: Clinical ChemistryTable 75: HematologyBody Weight

[0435] Body weight was assessed in male Cynomolgus monkeys having diet- induced obesity of age 14-19 years old (n=6). Monkeys were subcutaneously injected with 07 or 011 at 1 mg / kg and 3 mg / kg. Monkeys were fasted overnight before dosing. Body weight was measured on days 1 , 8, and 15 and percent change in body weight was calculated. Results are shown in Tables 76 and 77, respectively.Table 76: Body Weight (kg)Table 77: Body Weight (% Change)Complete Blood Count

[0436] Complete blood count (CBC) was assessed on days 1 , 8, and 12. Results are detailed in Tables 78-83.Table 78: Complete Blood Count Day 1 (Part 1 )Table 79: Complete Blood Count Day 1 (Part 2)Table 80: Complete Blood Count Day 8 (Part 1 )Table 81 : Complete Blood Count Day 8 (Part 2)Table 82: Complete Blood Count Day 12 (Part 1 )Table 83: Complete Blood Count Day 12 (Part 2)Clinical Chemistry

[0437] Clinical chemistry, including triglycerides, creatine kinase, lactate dehydrogenase, alanine amino transferase, aspartate amino transferase, bilirubin, alkaline phosphatase, total protein, albumin, globulin, glucose, urea nitrogen, creatine, urea acid, and C-reactive protein was assessed in monkey serum on days 1 , 8 (2h), and 1 1 (2h). Results of each measurement are outlined in Tables 84-89.Table 84: Clinical Chemistry Day 1 (Part 1 )Table 85: Clinical Chemistry Day 1 (Part 2)Table 86: Clinical Chemistry Day 8 (Part 1 )Table 87: Clinical Chemistry Day 8 (Part 2)Table 88: Clinical Chemistry Day 12 (Part 1)Table 89: Clinical Chemistry Day 12 (Part 2)Food Intake

[0438] Food intake (g) was assessed in monkeys on days 2, 3,4,9,10,11, and 13-15. Results are detailed in Table 90.Table 90: Food Intake

[0439] Food intake was also assessed on days 1, 8, and 12 at 0.5-, 1-, 1.5-, 2-, 3-, 4-, 24-, 48-, and 72-hours post-dose.Results are detailed in Tables 91 and 92.Table 91 : Food intake Days 1 and 8Table 92: Food Intake Day 12Example 11: Acute Food Intake

[0440] Food intake was assessed in 6 diet-induced obese Cynomolgus monkeys (n=6). Monkeys were first administered saline on day 1 (D1 ) and food intake was measured (FIGS. 11 A-1 1 D). On day 8 and day 12, monkeys were administered 1 mg / kg 07 (Group 1 ; n=2), or 01 1 (Group 3; n=2) (FIGS. 12A-12H). Monkeys were fasted overnight prior to administration. Food was administered 2 hours after each dose and intake was measured at 0.5-, 1 -, 1.5-, 2-, 3-, 4-, 24-, 48-, and 72-hours after dosing. Group 2 monkeys demonstrated a decrease in food intake relative to saline dosing (FIGS. 13A-13D).Example 12: Caloric Intake, Body Weight, and Body CompositionFood Intake and Body Composition in Monkeys

[0441] Changes in caloric intake and body weight were assessed in diet-induced obese Cynomolgus monkeys (n=6). Monkeys were orally administered 10 mg / kg 07 (MC4R selective agonist). One day 15, dosing changed to 15 / mg / kg administered twice daily, and dosing was maintained until at least day 28 and monkeys were assessed until at least day 35. Control monkeys were administered saline. Daily caloric intake (FIGS. 14A), cumulative caloric intake (FIGS. 14B and 15A), percent change in caloric consumption, relative to baseline (FIGS. 14C, 15B), and caloric intake per body weight were measured in addition to food intake (see also FIGS. 15A-15J; Tables 93-11 1 ). Cumulative caloric intake and percent change in caloric intake, relative to baseline, were each reduced in the monkeys administered 07, relative to those administered saline. Changes in body composition and body weight were also assessed (Tables 113-1 15; FIGS. 16A-16G).Table 93: Animal Pre-screening and Day 1 Food IntakeTable 94: Days 2-4 Food IntakeTable 95: Days 5-7 Food IntakeTable 96: Days 8-10 Food IntakeTable 97: Days 1 1-13 Food IntakeTable 98: Day 14 Food IntakeTable 99: Days 15 and 16 Food IntakeTable 100: Days 17 and 18 Food IntakeTable 101 : Days 19 and 20 Food IntakeTable 102: Days 21 and 22 Food IntakeTable 103: Days 24 and 25 Food IntakeTable 104: Days 26 and 27 Food IntakeTable 105: Days 28 and 29 Food IntakeTable 106: Day 30 Food IntakeTable 107: Food Intake (Calorie) Prescreening and Days 1 -4Table 108: Days 5-10 Food Intake (Calorie)Table 109: Days 11-14 Food Intake (Calorie)Table 110: Days 15-22 Food Intake (Calorie)Table 111: Days 24-30 Food Intake (Calorie)Table 112: Body Composition at Baseline (Part 1 )Table 113: Body Composition at Baseline (Part 2)Table 114: Body Weight (kg) (Day 1 -22)Table 115: Body Weight (Percent Change)

[0442] Blood chemistry, clinical chemistry, gastric impact, and nausea levels were also assessed (Tables 1 16-127). Cage side observations showed no signs of gastric distress (assessed by stool changes) or nausea (assessed by food refusal).Table 116: Clinical Chemistry Day 1 (Part A)Table 1 17: Clinical Chemistry Day 1 (Part B)Table 1 18: Clinical Chemistry Day 15 (Part A)Table 119: Clinical Chemistry Day 15 (Part B)Table 120: Clinical Chemistry Day 29 (Part A)Table 121 : Clinical Chemistry Day 29 (Part B)Table 122: Complete Blood Count Day 1 (Part A)Table 123: Complete Blood Count Day 1 (Part B)Table 124: Complete Blood Count Day 15 (Part A)Table 125: Complete Blood Count Day 15 (Part B)Table 126: Complete Blood Count Day 29 (Part A)Table 127: Complete Blood Count Day 29 (Part B)Food Intake and Body Composition in Rats

[0443] Normalized cumulative food consumption (FIG. 15K) and percent change in body weight (FIG. 16K) were assessed in rats administered MC4R selective agonists (A07D, 07, 01 1 ) (n=5) or MC3R / MC4R co-agonists (010) compared to saline controls (n=4). For each treatment group, rats were subcutaneously administered 0.5 mg / kg of A07D, 07, 010, or 01 1 for days 1 -7 and 1 mg / kg for days 8-17. 01 1 and 07 did not appear to influence food consumption as a percent of food consumption in saline- treated rats, relative to 010 (FIG. 15K). At 17 days, 010 treated rats gained only about 0.64% of their body weight compared to saline, which gained about 8.98% body weight (**) (FIG. 16J). 010-treated rats gained less weight than 07-treated rats (****), A07D- treated rats (*), and 01 1 -treated rats (p=.066). 010, an MC3R / MC4R coagonist, also exhibited a stronger influence on caloric consumption, as measures by cumulative food consumption) than the MC4R selective agonists. However, both the MC4R selectiveagonists and the MC3R / MC4R coagonists were each more effective in reducing body weight relative to saline controls.

[0444] Rats were also assessed for blood glucose levels following subcutaneous administration of 1 mg / kg or 3 mg / kg A07D using an oral glucose tolerance test (OGTT). Blood glucose was monitored at day 0 (FIG. 19A), day 8 (FIG. 19B), and day 19 (FIG. 19C). Blood glucose was significantly reduced by day 8 in rats administered A07D at both 1 mg / kg and 3 mg / kg compared to saline controls (FIG. 19D).Example 13: Assessing BioavailabilitvA07D

[0445] Various pharmacokinetic parameters of A07D were assessed in the plasma of male cynomolgus monkeys fasted prior to dosing A07D at 1 mg / kg intravenously, 10 mg / kg orally, or 30 mg / kg orally. Results are shown in Table 128 and FIG. 22.Table 128: A07D Results

[0446] ND = Not determined (Parameters not determined due to inadequately defined terminal elimination phase).

[0447] BQL = Below the lower limit of quantitation (LLOQ).

[0448] If the adjusted rsq (linear regression coefficient of the concentration value on the terminal phase) is less than 0.9, T1 / 2 might not be accurately estimated.

[0449] If the % AUCExtra > 20%, AUCo-inf, Cl, MRTo-inf and Vdss might not be accurately estimated.

[0450] If the % AUMCExtra > 20%, MRTo-inf and Vdss might not be accurately estimated.

[0451] The adjusted linear regression coefficient of the concentration value on the terminal phase is less than 0.9, T1 / 2 might not be accurately estimated.

[0452] a: Bioavailability (%) was calculated using AUCo-inf (if all AUCExtra < 20%) or AUCo -last (if one or more AUCExtra > 20%) with Nominal Dose.07 & C29

[0453] Plasma concentration of 07 and C29 were next assessed up to 24 hours following oral administration to cynomolgus monkeys at 10 mg / kg or 30 mg / kg, results of which are shown in FIGS. 17 and 18.Example 14: Cardiac Effects07 & 011

[0454] Changes in cardiac effects were assessed in rats subcutaneously administered 07 or 01 1 at either 0.5 mg / kg, 1 mg / kg, or 3 mg / kg. Control rats were administered saline. Animal specifications are outlined in Table 129.Table 129: Animal SpecificationsAnimal Housing

[0455] 6-7 week old male SD rats were obtained and housed in a controlled environment (target conditions: temperature 20 to 24°C, relative humidity 30 to 70%). Temperature and relative humidity was monitored daily. An electronic time-controlled lighting system was used to provide a 12-hour light / 12-hour dark cycle. Rats were housed in plastic cages. Enrichment toys were provided. During the housing and study period, the rats were fed with normal chow and fresh water, ad libitum.Animal Acclimation

[0456] After arrival, the animals acclimated to environment for at least 5 days.Study Design

[0457] Before the experiment, the weight of each animal was measured and rats were be separated into different groups based on weight, with 3 rats per group (Table 130).Table 130: Study GroupsBlood Pressure and 2-Lead ECG Monitoring

[0458] After acclimatization, animals were anesthetized with urethane as well as subjected to femoral vein for drug injection and carotid common artery to measure blood pressure. Meanwhile, electrocardiogram (ECG) was detected by subcutaneous puncture needle electrodes. The body temperature of the rats was maintained at about 37°C during assessments and experimentation. The blood pressure (BP) and ECG was recorded for 15 minutes before administration and for 3 hours after administration continuously for each rat.Readouts

[0459] Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were recorded with blood pressure measurements.

[0460] QRS, ST, QT, P wave, T wave, and HR were assessed with ECG measurements.

[0461] Recording duration occurred from -15 min (pre-dose) to 180 min (after dosing).Blood Collection

[0462] After recording, animals were euthanized with CO2 immediately and blood was collected for in vitro analysis, including plasma corticosterone by ELISA Kit.Data Processing and Analysis

[0463] All values were expressed as mean ± SEM. The significances of the differences among groups and within groups was evaluated by one-way ANOVA followed by Dunnett’s test using Graph Pad statistic software. A p value of less than 0.05 was considered statistically significant. Results for the BP analysis are shown for all groups in Tables 131 -133. ECG results are shown in Tables 134-138.Table 131 : Blood Pressure Analysis (Part 1 )Table 132: Blood Pressure Analysis (Part 2)Table 133: Blood Pressure Analysis (Part 3)Table 134: ECG Results (Part 1 )Table 135: ECG Results (Part 2)Table 136: ECG Results (Part 3)Table 137: ECG Results (Part 4)Table 138: ECG Results (Part 5)

[0464] No significant changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), nor heart rate (HR) were observed in rats administered 07 or 01 1 at any dose, relative to controls. Comparably, setmelanotide-treated animals showed at some doses, there were changes in QTc, suggesting altered cardiac repolarization. (FIGS. 20A-20D).A07D (A3; SEQ ID NO: 31)

[0465] The effect of the melanocortin analogs on cardiac activation in rats was tested using A3 according to the following procedure. Baseline measurements of heart rate, systolic blood pressure, and diastolic blood pressure of rats were taken 15 minutes prior to administration of A3. The rats were then administered saline, 3 mg / kg A3, or 6 mg / kg A3 via subcutaneous injection and the heart rate, systolic blood pressure, and diastolic blood pressure were measure at the following time points post injection: 5 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes, and 180 minutes.

[0466] FIGS. 20E-20G show the cardiac activation data from 15 minutes before subcutaneous injection of A3 to 180 minutes after injection of A3. As shown in FIG. 20E, the heart rate of rats administered 3 mg / kg A3 (G1 ) decreased directly after injection, increased steadily from 30 minutes to 120 minutes, and then decreased again at 180 minutes to just slightly above the starting heart rate (i.e., at -15 min). Rats administered 6 mg / kg A3 (G2) maintained a steady heart rate until 120 minutes after injection when an increase in heart rate may be seen, however, the final heart rate of G2 rats was similar to that of G1 and control (G3) rats.

[0467] As may be seen in FIG. 20F the systolic blood pressure (SBP) of the rats in each group was similar for all time points, with a slight increase overall after injection for all three groups. The diastolic blood pressure (DBP) of rats administered 3 mg / kg A3 and 6 mg / kg A3 was higher than the diastolic blood pressure of the control rats at all time points post injection, however, no group of rats had a diastolic blood pressure above 100 at any time point (FIG. 20G).

[0468] This data suggests that melanocortin analogs in accordance with the present technology such as A3 avoid cardiac activation, which has been seen in earlier peptide and small molecule agonists of the melanocortin receptors.Example 15: Pharmacokinetic Assessment of Non-Naturally Occurring Melanocortin Analogs Following Subcutaneous Administration to RatsStudy Objective

[0469] The objective of this study is to determine the pharmacokinetics of non- naturally occurring melanocortin analogs of the present technology following subcutaneous administration in male rats. In rats, the test article will be monitored in plasma for up to 24 hours post each dose. Study design and sample collection will be conducted as outlined in Table 139 and 140.Table 139. Study DesignTable 140. Sample CollectionsE: Anticoagulant: Potassium (K2) EDTA;P: plasmaC: cerebrospinal fluid (CSF)

[0470] Dose Solution Analysis Samples: After each dose preparation, remove approximately 0.5 mL aliquots from the formulations, transfer the aliquots into amber HPLC vials and stored at -60°C or lower until assayed in duplicate for dose validation.

[0471] Disposition of Remaining Test Article Formulations: Remaining formulations will be stored at -60°C or lower.

[0472] Disposition of Remaining Test Article (dry powder or solid): Remaining test article will be stored at room temperature desiccated, and protected from light until shipment or discard.

[0473] Animals will be fasted overnight through 4 hours post dosing.Vehicle and Formulation Preparation:

[0474] Appropriate amount of test article will be accurately weighed and mixed with appropriate volume of vehicle to get a clear solution or suspension.

[0475] Formulation samples will be removed from each of the formulation solutions, transferred into 1 .5 mL of polypropylene microcentrifuge tubes and run dose validation by LC / UV or LC-MS / MS.Animal Specifications: Rats

[0476] Rat specifications are outlined in Table 141 .Table 141 . Rat SpecificationsObservations and Examinations

[0477] Clinical Observations: All animals will be observed at dosing and each scheduled collection. All abnormalities will be recorded.

[0478] Body Weight: All animals will be weighed on the dosing day prior to dosing to determine the dose volume to be administered.Sample Collection and Processing

[0479] Blood Sample Collection and Process: At least 0.1 mL blood will be collected at each time point. All blood samples will be collected via jugular vein. All blood samples will be transferred into low binding EP tube with anticoagulant (0.5 M Potassium (K2) EDTA will be pre-added as a ratio of 50:1 for blood: anticoagulant), 0.05% Triton X-100 (e.g., 100uL Blood+2uL 2.5% Triton X-100) will be used for desorption the blood samples will be placed on wet ice.

[0480] Blood samples will be centrifuged within 1 hr of collection at 3,200 g 4°C for 10 minutes. Following centrifugation, plasma samples will be transferred into their respective pre-labeled low binding EP tube and immediately frozen over dry ice. The plasma samples will be stored lower than -60°C until bioanalysis.

[0481] LC-MS / MS method development:

[0482] A LC-MS / MS method for the quantitative determination of test compound in biological matrix will be developed.

[0483] N in 1 cassette LC-MS / MS method can be developed for samples coming from different studies as long as these studies belong to the same sponsor.

[0484] Cassette administration assay could be performed if the mass difference (AMass) among different analytes is >4 Da. In this case, interference evaluation is not necessary.

[0485] If AMass among different analytes is less than 4 Da, there is a potential risk that interference would occur during LC-MS / MS analysis. If such kind of cassette assay is still requested by client, interference among analytes will not be evaluated but the LC separation of those analytes by using a generic method will be attempted.

[0486] Sample analysis:

[0487] A calibration curve with at least 6 non-zero calibration standards will be applied for each batch including LLOQ.

[0488] If sample number within a batch is < 12, at least one set of standard curves separated with two parts through begin and end of the sequence should be included in the run and QCs are not required. The recommended injection order is C8, C6, C4, C2, study samples, C7, C5, 03, C1 .

[0489] If sample number within a batch is > 12, one standard curve and two sets of QCs with low, middle and high concentrations will be applied for bioanalysis. Meanwhile, QCs number should be more than 5% of study sample number.

[0490] Samples, coming from one client with the same type of matrix in different studies, are allowed to be quantified in one analysis run by using the developed N in 1 cassette LC-MS / MS method.

[0491] Acceptance criteria:

[0492] (1 ) Linearity: At least 75% of the calibration standards should fall within±20% of their nominal values for biofluid and within ±25% of their nominal values for tissue and feces samples. If the endpoints, such as LLOQ and ULOQ, on the calibration curve are eliminated, the calibration curve will be truncated. The truncated calibration curve should consist of at least 75% of the initial STDs.

[0493] (2) Accuracy: At least 67% of QCs should fall within ±20% of their nominal values for biofluid and within ±25% of their nominal values for tissue and feces samples. At least half of QCs at each concentration should be passed.

[0494] (3) Specificity: The mass response of analyte in the double blank and blank should be < 50% LLOQ.

[0495] (4) Sensitivity: The LLOQ will be tried to target < 3 ng / mL. Any adjustment of LLOQ will be informed to client in advance.

[0496] (5) Carryover: The mean calculated carryover peak area in the double blanks or blanks immediately after the highest standard injection should be less than that of LLOQ. If the carryover couldn’t meet the criteria, the impact of the carryover on unknown samples should be re-evaluated according to the below procedure:

[0497] Carryover should be re-evaluated based on absolute carryover. Absolute carryover is calculated by carryover contribution multiplies carryover impact, where the carryover contribution is calculated by the area ratio of the double blank or blank with the highest carryover (Area max of carryover blank) to the ULOQ with the minimum calculated value (Area min of ULOQ), and the carryover impact is calculated by the area ratio of one injection (Area of one injection) to the following injection (Area of the following injection). The absolute carryover should be below the acceptable accuracy of the studies (e.g., 20% or 25%).

[0498] Carryover contribution = Areamax of carryover blank / Areamin of ULOQ Carryover impact = Area of one injection / Area of the following injection Absolute carryover = Carryover contribution * Carryover impactData Analysis

[0499] Preliminary plasma and cerebrospinal fluid (CSF) results after 24 hours of subcutaneous (SC) administration of A07D in Rats are shown in Table 142 and Table 143. Graphs of plasma concentration and CSF concentration in Rats are shown in FIGS 21 A-21 D.Table 142. Concentration of A07D in plasma and CSF of Rats over timeND = not determinedTable 143. Plasma Pharmacokinetic Results of A07D in Rats after 24 hours

[0500] Dose proportionality of A07D in male rats following a single subcutaneous administration in Rats is shown in Table 144.Table 144. Dose Proportionality of A07D in Rats after a single SC administrationExample 17: Effects of A07D in the Expression of Morphine Conditioned Place Preference (CPP)

[0501] The non-naturally occurring melanocortin analogs of the present technology are share structural similarities with A07D, which has the sequence: Ac-Nle- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 31 ). For example, the melanocortin analogs of the present technology include one or more of the following features: Pro at R3, dPhe at R4; lactam cyclization; and dVal-dPro-NH2 C-terminus. Without intending to be limiting, these features, and in particular, the motif Pro-dPhe, and derivatives thereof, such as, for example, Pro-p(F)dPhe, impart the melanocortin analogs with partial agonism on the MC3R and full agonism on the MC4R. Accordingly, effects of A07D on morphine preference was assessed in rats using a CPP assay (FIG. 23A). Rats were habituated in animal facility for 7 days and were handled for 1 -2 minutes per day for 3 days before pre-test.

[0502] For pre-testing, rats were allowed to freely explore both sides of the box for 15 min to rule out a preference for either side (rats with a CPP score >+150 or < -150were excluded from the study). After pre-test, group assignment was conducted within each group according to the pre-test results such that morphine was paired with the less-preferred compartment.

[0503] Following the pretest phase, rats underwent place conditioning for 8 days, with alternating treatment-compartment pairings. For a conditioning session, saline (2 mL / kg, intraperitoneal injection (i.p)) or morphine (10 mg / kg, i.p.) was administered, and rats were confined to the paired compartment for 45 minutes.

[0504] For post-testing, one day later, rats were randomly placed into one compartment and have access to both compartments during the 15-minute test period, and the time spend in each compartment was recorded. Animals that with a CPP score > 100 in the morphine group were included for the further tests.

[0505] In the Expression test 1 , A07D at 3 mg / kg and vehicle were administered subcutaneously (s.c) once 2 hours before the CPP expression test. The CPP score was defined as the time (in seconds) spent in the morphine-paired compartment minus the time spent in the saline-paired compartment during the CPP test. Groups included group 1 (vehicle + saline administration), group 2 (vehicle + morphine administration), and group 3 (A07D + morphine administration) (N = 10 rats per group).

[0506] For the Expression test 2, 24 hours later, A07D at 3 mg / kg was administered (s.c) once 1 hour before the CPP expression test. The CPP score was defined as the time (in seconds) spent in the morphine-paired compartment minus the time spent in the saline-paired compartment during the CPP test.

[0507] Data were analyzed by the two-way ANOVA followed by Bonferroni’s pos hoc analysis.Results

[0508] There was no difference in the pre-test for all groups (FIG. 23B). In the posttest, morphine-conditioned groups showed significant increased CPP score compared with saline-conditioned group (p<0.0001 ). There was no difference between vehicle + morphine group and A07D + morphine group in the post-test (p>0.9999). In the Expression test 1 , A07D at the dose of 3 mg / kg almost significantly reduced the morphine CPP score when administered 2 hours prior to the test (p = 0.08). In the Expression test 2, A07D at the dose of 3 mg / kg significantly reduced the morphine CPPscore when administered 1 hour prior to the test (p = 0.01 ). Results are further detailed in Tables 145 and 146.

[0509] A07D significantly decreased the expression of morphine CPP in rats, indicating a potential effect of A07D in attenuating morphine addiction-related behaviors.Table 145: Summary Statistics for CPP Scores (N=10 per group)Table 146: Individual CPP ScoresExample 18: Assessing absorption, distribution, metabolism, and excretion of non-naturallv occurring melanocortin analogs

[0510] Non-naturally occurring melanocortin analogs of the present technology, A07D, 07, 011 , and M1 (Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2), were assessed for solution properties, in vitro absorption, and in vitro metabolism for absorption, distribution, metabolism, and excretion (ADME) properties. Various ADME outcomes are outlined in Table 147 ([Test]: Test Compound Concentration; Comp.: Compound; Rep: replicate; recov.: recovery; T1 / 2: half-life (minutes); Avg.: mean; Perm.: permeability).Aqueous Solubility

[0511] Aqueous solubility (pM) was determined by comparing the peak area of the principal peak in a calibration standard (200 pM) containing organic solvent (methanol / water, 60 / 40, v / v) with the peak area of the corresponding peak in a buffer sample. Additionally, chromatographic purity (%) was defined as the peak area of the principal peak relative to the total integrated peak area in the HPLC chromatogram of the calibration standard. A chromatogram of the calibration standard of each test compound, along with a UV / VIS spectrum with labeled absorbance maxima, was generated.HPLC-UV Screen

[0512] A chromatogram of the test compound (200 pM) along with a UV / VIS spectrum with labeled absorbance maxima, was generated.Protein Binding

[0513] The peak areas of the test compound in the buffer and test samples were used to calculate percent binding and recovery according to the following formulas:Protein binding (%)= (AreaP-AreabAreaP)*100Recovery (%)=((AreaP+Areab) / Areac)*100where:AreaP= Peak area of analyte in protein matrixAreab = Peak area of analyte in bufferAreac= Peak area of analyte in control samplePartition Coefficient

[0514] The total amount of compound was determined as the peak area of the principal peak in a calibration standard (100 pM) containing organic solvent (methanol / water, 60 / 40, v / v). The amount of compound in buffer was determined as the combined, volume-corrected, and weighted areas of the corresponding peaks in the aqueous phases of three organic-aqueous samples of different composition. An automated weighting system was used to ensure the preferred use of raw data from those samples with well quantifiable peak signals. The amount of compound in organic was calculated by subtraction. Subsequently, LogD was calculated as the Log10 of the amount of compound in the organic phase divided by the amount of compound in the aqueous phase.Half-Life Determination

[0515] At the end of the incubation at each of the time points, an equal volume of an organic mixture (acetonitrile / methanol, 50 / 50, v / v) was added to the incubation mixture. Samples were analyzed by HPLC-MS / MS and corresponding peak areas were recorded for each analyte. The ratio of precursor compound remaining after each time point relative to the amount present at time 0, expressed as percent, is reported as chemical stability. The half-life (T1 / 2) was estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) versus time, assuming first- order kinetics.ADME-Tox: In Vitro AbsorptionPermeability

[0516] The apparent permeability coefficient (Papp) of the test compound was calculated as follows:Papp(CITl / s)=(VR-CR,end / At)-(1 / A*(CD,mid— CR.mid)) where:VR is the volume of the receiver chamber.C ,end is the concentration of the test compound in the receiver chamber at the end time point.At is the incubation time.A is the surface area of the cell monolayer.CD, mid is the calculated mid-point concentration of the test compound in the donor side, which is the mean value of the donor concentration at time 0 minute and the donor concentration at the end time point.CR.mid is the mid-point concentration of the test compound in the receiver side, which is one half of the receiver concentration at the end time point. Concentrations of the test compound were expressed as peak areas of the testRecovery of the Test Compound from the Permeability Assay

[0517] The recovery of the test compound was calculated as follows:Recovery (%)=((VD-CD,end+VR-CR,end) / (VD’CDo))* 100 where: VD and VR are the volumes of the donor and receiver chambers, respectively.CD, end is the concentration of the test compound in the donor sample at the end time point.CR.end is the concentration of the test compound in the receiver sample at the end time point.CDO is the concentration of the test compound in the donor sample at time zero. Concentrations of the test compound are expressed as peak areas of the test compound.Fluorescein Assessment for Permeability Assays

[0518] Fluorescein was used as the cell monolayer integrity marker. Fluorescein permeability assessment (in the A-B direction at pH 7.4 on both sides) was performed after the permeability assay for the test compound. The cell monolayer that had a fluorescein permeability of less than 1 .5 x 10-6cm / s for Caco-2 and MDR1 -MDCKII cells and 2.5 x 10-6cm / s for MDCKII cells was considered intact, and the permeability result of the test compound from intact cell monolayer is reported.ADME-Tox: In Vitro MetabolismIntrinsic Clearance (microsomes, S9, cryopreserved hepatocytes, recombinant CYP, recombinant UGT)

[0519] Metabolic stability, expressed as percent of the parent compound remaining, was calculated by comparing the peak area of the compound at the time point relative to that at time-0. The half-life (T1 / 2) was estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) vs. time, assuming first-order kinetics. The apparent intrinsic clearance (CLint, in pL / min / pmol, pL / min / mg or pL / min / Mcell) was calculated according to the following formula:CLint = 0.693 / (Ti / 2*(mg protein / pL or million cells / pL or pmol CYP isoyme / pL))Table 147: ADME Assessment of Non-Naturally Occurring Analogs and ReferenceCompoundsAdditional Embodiments

[0520] Various embodiments of the present technology are set forth below in paragraphs

[0521] to

[0535] :

[0521] Embodiment 1 . A non-naturally occurring melanocortin analog comprising a sequence according to Formula (IC):R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IC), wherein:R1is Nle;R2is Asp or Glu;R3is Pro;R4is p(F)dPhe or dPhe;R5is Arg;R6is Trp;R7is Orn;Y1is dVal;Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7, provided that: when R4is dPhe, then R2is Glu.

[0522] Embodiment 2. The non-naturally occurring melanocortin analog of embodiment 2, comprising a sequence according to Formula (IC), wherein:R1is Nle;R2is Asp or Glu;R3is Pro;R4is p(F)dPhe or dPhe;R5is Arg;R6is Trp;R7is Orn;Y1is dVal;Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 23).

[0523] Embodiment 3. The non-naturally occurring melanocortin analog of embodiment 1 or 2, wherein the sequence of Formula (IC) is selected from the group consisting of:Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 216);Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 217); andAc-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 218), wherein c represents cyclization through R2and R7via a lactam bond.

[0524] Embodiment 4. The non-naturally occurring melanocortin analog of any one of embodiments 1 -3, wherein the sequence of Formula (IC) is cyclized through a lactam bond between Glu at R2and Orn at R7.

[0525] Embodiment 5. The non-naturally occurring melanocortin analog of embodiment 4, wherein the sequence of Formula (IC) is:Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 216); or Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 218), wherein c represents cyclization through R2and R7via a lactam bond.

[0526] Embodiment 6. The non-naturally occurring melanocortin analog of any one of embodiments 1 -3, wherein R4is p(F)dPhe.

[0527] Embodiment 7. The non-naturally occurring melanocortin analog of embodiment 6, wherein the sequence of Formula (IC) is:Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 217);Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 218), wherein c represents cyclization through R2and R7via a lactam bond.

[0528] Embodiment 8. The non-naturally occurring melanocortin analog of embodiment 7, wherein the sequence of Formula (IC) is: Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 218), wherein c represents cyclization through R2and R7via a lactam bond.

[0529] Embodiment 9. The non-naturally occurring melanocortin analog of any one of embodiments 1 -3, wherein R4is dPhe.

[0530] Embodiment 10. The non-naturally occurring melanocortin analog of embodiment 4, wherein the sequence of Formula (IC) is: Ac-Nle-c[Glu-Pro-dPhe-Arg- Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 216), wherein c represents cyclization through R2and R7via a lactam bond.

[0531] Embodiment 11 . The non-naturally occurring melanocortin analog of any one of embodiments 1 -10, wherein the non-naturally occurring melanocortin analog binds at least a portion of a melanocortin receptor.

[0532] Embodiment 12. The non-naturally occurring melanocortin analog of embodiment 1 1 , wherein the non-naturally occurring melanocortin analog binds one or more amino acids of the melanocortin receptor.

[0533] Embodiment 13. The non-naturally occurring melanocortin analog of embodiment 12, wherein the non-naturally occurring melanocortin analog binds two or more amino acids of the melanocortin receptor.

[0534] Embodiment 14. The non-naturally occurring melanocortin analog of any one of embodiments 1 1 -13, wherein the non-naturally occurring melanocortin analog comprises a dissociation constant (Kd) value for the melanocortin receptor or the one or more amino acids thereof that is less than that of a conventional melanocortin analog

[0535] Embodiment 15. The non-naturally occurring melanocortin analog of any one of embodiments 1 1 -14, wherein the melanocortin receptor is a melanocortin 3 receptor or a melanocortin 4 receptor.

[0536] From the foregoing, it will be appreciated that specific embodiments of the present technology have been described herein for purposes of illustration, but that various modifications may be made without deviating from the scope of the present technology. Accordingly, the present technology is not limited except as by the appended claims.

Claims

CLAIMSI / We claim:

1. A non-naturally occurring melanocortin analog comprising a sequence according to Formula (IC):R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IC), wherein:R1is Nle;R2is Asp or Glu;R3is Pro;R4is p(F)dPhe or dPhe;R5is Arg;R6is Trp;R7is Orn;Y1is dVal;Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7, provided that: when R4is dPhe, then R2is Glu.

2. The non-naturally occurring melanocortin analog of claim 2, comprising a sequence according to Formula (IC), wherein:R1is Nle;R2is Asp or Glu;R3is Pro;R4is p(F)dPhe or dPhe;R5is Arg;R6is Trp;R7is Orn;Y1is dVal;Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 23).

3. The non-naturally occurring melanocortin analog of claim 1 or 2, wherein the sequence of Formula (IC) is selected from the group consisting of:Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 216); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 217); andAc-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 218), wherein c represents cyclization through R2and R7via a lactam bond.

4. The non-naturally occurring melanocortin analog of any one of claims 1 - 3, wherein the sequence of Formula (IC) is cyclized through a lactam bond between Glu at R2and Orn at R7.

5. The non-naturally occurring melanocortin analog of claim 4, wherein the sequence of Formula (IC) is:Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 216); or Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 218), wherein c represents cyclization through R2and R7via a lactam bond.

6. The non-naturally occurring melanocortin analog of any one of claims 1 - 3, wherein R4is p(F)dPhe.

7. The non-naturally occurring melanocortin analog of claim 6, wherein the sequence of Formula (IC) is: Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 217);Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 218), wherein c represents cyclization through R2and R7via a lactam bond.

8. The non-naturally occurring melanocortin analog of claim 7, wherein the sequence of Formula (IC) is: Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 218), wherein c represents cyclization through R2and R7via a lactam bond.

9. The non-naturally occurring melanocortin analog of any one of claims 1 - 3, wherein R4is dPhe.

10. The non-naturally occurring melanocortin analog of claim 4, wherein the sequence of Formula (IC) is: Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 216), wherein c represents cyclization through R2and R7via a lactam bond.11 . The non-naturally occurring melanocortin analog of any one of claims 1 - 10, wherein the non-naturally occurring melanocortin analog binds at least a portion of a melanocortin receptor.

12. The non-naturally occurring melanocortin analog of claim 11 , wherein the non-naturally occurring melanocortin analog binds one or more amino acids of the melanocortin receptor.

13. The non-naturally occurring melanocortin analog of claim 12, wherein the non-naturally occurring melanocortin analog binds two or more amino acids of the melanocortin receptor.

14. The non-naturally occurring melanocortin analog of any one of claims 1 1- 13, wherein the non-naturally occurring melanocortin analog comprises a dissociationconstant (Kd) value for the melanocortin receptor or the one or more amino acids thereof that is less than that of a conventional melanocortin analog.

15. The non-naturally occurring melanocortin analog of any one of claims 1 1 - 14, wherein the melanocortin receptor is a melanocortin 3 receptor or a melanocortin 4 receptor.

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