Non-naturally occurring melanocortin analogs with expanded cycles and / or an extended n-terminus for modulating gastrointestinal disorders

Abstract

The present technology comprises non-naturally occurring melanocortin analogs or pharmaceutically acceptable salts, solvates, or stereoisomers thereof and compositions comprising the same. The non-naturally occurring melanocortin analogs may be agonists of melanocortin 1 with sub-micromolar or low-nanomolar binding activity. In some embodiments, the non-naturally occurring melanocortin analogs are formulated for delivery to a subject in need thereof.

Description

Docket No.: 183B-416029-WO NON-NATURALLY OCCURRING MELANOCORTIN ANALOGS WITH EXPANDED CYCLES AND / OR AN EXTENDED N-TERMINUS FOR MODULATING GASTROINTESTINAL DISORDERS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 683,669, filed August 15, 2024; U.S. Provisional Patent Application No.63 / 683,633, filed August 15, 2024; U.S. Provisional Patent Application No.63 / 683,637, filed August 15, 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 is hereby incorporated by reference in its entirety. created on August 14, 2025 is titled “183B-416029-WO_SL.xml” and is 337,260 bytes in size. BACKGROUND

[0003] Melanocortins are a group of small peptides that bind to a family of five known melanocortin receptors (MC1R through MC5R). They are derived from a common precursor protein, pro-opiomelanocortin (POMC), which is expressed in the neurons of the central and peripheral nervous system, and in the pituitary gland. The proteolytic cleavage of POMC results in α-, β- and γ-melanocortin and adrenocorticotrophic hormone (ACTH), in addition to several other biologically important peptides.

[0004] Melanocortin analogs have been synthesized for the potential regulation and treatment of many conditions, including weight regulation (e.g., obesity, anorexia, and cachexia), hormonal secretion, and hyposecretion of many exocrine glands. However, in regulating these physiological effects, melanocortin analogs have also been shown to cause certain side effects, such as, for example hypertension and cardiac arrhythmias. -1- 168588233.2Docket No.: 183B-416029-WO

[0005] Despite recent attempts to reduce melanocortin peptide side effects or enhance melanocortin in vivo activity, there still exists a need for highly stable and selective melanocortin analogs in the treatment and prevention of various melanocortin-related diseases. SUMMARY

[0006] Provided herein are non-naturally occurring melanocortin analogs comprising a sequence of Formula (I), X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(I), wherein: X1is selected from the group consisting of norleucine (Nle), D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), tryptophan (Trp), and parafluoro-D-phenylalanine (p(F)dPhe); R4is selected from the group consisting of D-2’-naphthylalanine (dNal(2’)), p(F)dPhe, dPhe, His, Arg, and Trp; R5is selected from the group consisting of Arg, p(F)dPhe, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, Lys, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), dPhg, and p(F)dPhe; R7is absent or Trp; R8is selected from the group consisting of ornithine (Orn), 2,4-diaminobutyric acid (Dab), Asp, Dap, and Lys; -2- 168588233.2Docket No.: 183B-416029-WO Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, a lactam bridge between R1and R8, when R1is Asp, R2is absent, R6is Lys or Ala, R7is Trp, R4is p(F)dPhe, and R8is Dab or Orn, a lactam bridge between R1and R8, when R1is Asp, R2and R7are absent, R4is dPhe or dNal(2’), and R8is Lys, and a lactam bridge between R1and R8, when R1is Glu, R2and R7are absent, R4is His or Arg and R8is Orn, provided that: when R4is dPhe, then X1is dAsp and X2-X3are absent, when R4is dNal(2’), then (i) X1is dAsp and X2is not dAla when X3is absent, (ii) X1is dOrn, X2is absent or dAla, and X3is absent (iii) X1is dPhe and X2is Gly or dAla, or (iv) X1is dPhg, X2is dAla, and X3is absent, when R4is p(F)dPhe, then (i) R5is Arg and R3and R6are not Arg, wherein when R6is Ala or dAla, then R8is Dab or Asp, when R6is Lys, then R8is Dab or Orn, and when R6is Dap, then R8is Dap, or (ii) R5is not Arg, wherein when R5is dPhe, then R8is not Dap, and when R4is Arg or His, then R5is not His, and R6is not Arg.

[0007] Further provided herein are composition comprising a non-naturally occurring melanocortin analog as described herein. DETAILED DESCRIPTION

[0008] The present technology provides non-naturally occurring melanocortin analogs and pharmaceutically acceptable salts, solvates, and stereoisomers thereof, referred to herein collectively as melanocortin analogs. The melanocortin analogs of the present technology may selectively bind the melanocortin 1 receptor over other melanocortin -3- 168588233.2Docket No.: 183B-416029-WO receptors, e.g., the melanocortin 2, melanocortin 3, melanocortin 4, and melanocortin 5 receptors.

[0009] Each of the melanocortin analogs may have one or more beta hairpin (β-hairpin) and / or beta turn (β-turn) structures. In general, cyclization such as, for example, via a disulfide or lactam bond, may stabilize beta-turns, structurally rigid amino acids, such as, for example, proline, and / or the presence of D-amino acids may induce and / or stabilize beta- turns.

[0010] The non-naturally occurring melanocortin analogs of the present technology include one or more of the following features: an N-terminus that stabilizes the melanocortin analog; a pharmacophoric region that binds to one or more melanocortin receptor; and a C- terminus that provides enhanced transport and / or resistance to degradation. The melanocortin analogs may be linear or cyclized.

[0011] The following description is merely exemplary in nature and is not intended to limit the present technology, its applications, or its uses. 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.

[0012] 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 or functions 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. -4- 168588233.2Docket No.: 183B-416029-WO Definitions

[0013] 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.

[0014] 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.

[0015] 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, it modifies that range by extending the boundaries above and below the numerical values set forth.

[0016] 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.

[0017] As used herein, a “pharmaceutically acceptable carrier” of the first or the second 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, 21st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, -5- 168588233.2Docket No.: 183B-416029-WO 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 other carbohydrates 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 second 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.

[0018] “Melanocortin analogs,” “melanocortin 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 non-naturally occurring melanocortin peptides and truncated and / or modified versions of melanocortin full-length protein or peptides. For example, the full-length pro-opiomelanocortin 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 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. “Melanocortin peptides” can be structurally similar and / or functionally similar to biological melanocortin proteins in their ability to bind melanocortin receptors. Further, the melanocortin analogs generally -6- 168588233.2Docket No.: 183B-416029-WO contain the pharmacophore: His-Phe-Arg-Trp (SEQ ID NO: 1) or a modified version thereof, or a structural or functional peptide mimetic thereof.

[0019] 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 can be small peptides or organic molecules designed to mimic the appearance or function (including activation or deactivation of receptor activity) of the melanocortin pharmacophore core sequence peptide.

[0020] A “melanocortin receptor agonist” or “melanocortin agonist” is a naturally occurring substance or manufactured drug substance or composition that can interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor.

[0021] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating and the like.

[0022] The “peptides” described herein can 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.

[0023] 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 -7- 168588233.2Docket No.: 183B-416029-WO “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.

[0024] 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.

[0025] “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 α-amino acids differ in the side-chain moiety that is attached to the α-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.

[0026] 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 -8- 168588233.2Docket No.: 183B-416029-WO amino acids. It further includes side chain moieties in modified naturally 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 disclosed herein 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.

[0027] 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.

[0028] In the peptides described herein, conventional amino acid residues have their conventional meaning as given in Chapter 2400, of the Manual of Patent Examining Procedure, 8th Ed. Thus, “Ala” is alanine; “Arg” is arginine; “Asn” is asparagine; “Asp” is aspartic acid; “Cys” is cysteine; “Gln” is glutamine; “Glu” is glutamic acid; “His” is histidine; “Ile” is isoleucine; “Leu” is leucine; “Lys” is lysine; “Met” is methionine; “Phe” is phenylalanine; “Pro” is proline; “Ser” is serine; Thr is threonine; “Trp” is tryptophan; “Tyr” is tryosine; and “Val” is valine. Unless otherwise indicated, all amino acids abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof can be used. Thus, for example, “L-Phe” or “lPhe” is L-phenylalanine; “D-Phe” or “dPhe” is D- phenylalanine; dVal is D-valine; dPro is D-proline; “D- / L-Phe” or “d / lPhe” is D-phenylalanine, L-phenylalanine, or combinations thereof; “Phe” is also D-phenylalanine, L-phenylalanine, or combinations thereof, and so on.

[0029] An alpha (α)-amino acid has the generic formula H2N—CαHR—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 α-carbon). Other types of amino acids exist when the amino group is attached to a different carbon atom. -9- 168588233.2Docket No.: 183B-416029-WO

[0030] When β-amino acids are incorporated into peptides, two main types of β- peptides exist: those with the side chain residue, R, on the carbon next to the amine are called β3peptides and those with the side chain residue on the carbon next to the carbonyl group are called β2amino acids. Further, β-amino acids may adopt L- or D- stereochemistry. Unless otherwise indicated, all β-amino acid abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof.

[0031] Gamma (γ)-amino acids are amino acids with the carbon atom to which the amino group attaches is separated from the carboxylate moiety by two carbon atoms.

[0032] 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” and “c” refers to a cyclic structure. “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 amidated C-terminus.

[0033] Additional abbreviations are used as follows: Orn is ornithine; dOrn is D- ornithine; Dab is 2,4-diaminobutyric acid; dDab is 2,4-D-diaminobutyric acid; Dap is 2,3- diaminopropionic acid; dDap is 2,3-D-diaminopropionic acid; Aad is aminoadipic acid; Phg is phenylglycine; dPhg is D-phenylglycine; dNal(2’) is D-2’-naphthylalanine; and p(F)dPhe is para-fluoro-D-phenylalanine.

[0034] 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.”

[0035] 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.

[0036] An “amine” includes compounds that contain an amine group (—NH2).

[0037] 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. -10- 168588233.2Docket No.: 183B-416029-WO

[0038] 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.”

[0039] “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 melanocortin peptide by physiological enzymes and other factors, in such a manner or to a degree that side effects appear. According to one aspect, a 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 melanocortin analog that lacks a C-terminal extension.

[0040] 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

[0041] Non-naturally occurring melanocortin analogs described herein may be selective for the melanocortin 1 receptor over other melanocortin receptors, i.e., the melanocortin 2, melanocortin 3, melanocortin 4, and melanocortin 5 receptors. Some of the melanocortin analogs bind only the melanocortin 1 receptor. Alternatively, some of the melanocortin analogs bind the melanocortin 1 receptor with substantially greater affinity than the melanocortin 5 receptor and exhibit no binding on the other melanocortin receptors.

[0042] The non-naturally occurring melanocortin analogs of the present technology may be full agonists 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 80%. -11- 168588233.2Docket No.: 183B-416029-WO

[0043] The non-naturally occurring melanocortin analogs of the present technology may be partial agonists of one or more melanocortin receptor. A partial agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect Emax agonist value of less than 80%.

[0044] 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 agonist (e.g., a full agonist or a partial agonist). Similarly, 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 antagonist (e.g., a full antagonist or a partial antagonist).

[0045] The non-naturally occurring melanocortin analogs of the present technology may be one or more of (i) a full MC1R agonist and a partial MC5R agonist; (ii) a full MC1R antagonist having no activity on MC5R; (iii) a partial MC1R antagonist having no activity on MC5R; (iv) a full MC1R agonist and a full MC5R agonist demonstrating substantially greater binding affinity for MC1R; or (v) a partial MC1R agonist and a partial MC5R agonist demonstrating substantially greater binding affinity for MC1R.

[0046] The non-naturally occurring melanocortin analogs in accordance with the present technology may have 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 MC1R. For example, in some embodiments, the non-naturally occurring melanocortin analogs comprise one or more of (i) blood brain barrier passage capabilities, (ii) enhanced epithelial and / or gastrointestinal transport; or (iii) degradation resistance. In some embodiments, the non-naturally occurring melanocortin analogs comprise two or more of (i)-(ii). In some embodiments, the non- naturally occurring melanocortin analogs comprise each of (i)-(iii). Accordingly, in some embodiments, the melanocortin analogs include a stabilizing N-terminus, and / or a C- terminus that provides enhanced transport of the analog. In some embodiments, melanocortin analogs include a D-valine-D-proline (dVal-dPro) chain as their C-terminus, which may provide enhanced transport and resistance to degradation Additionally, in some embodiments, the melanocortin analogs have one or more beta hairpin (β-hairpin) and / or -12- 168588233.2Docket No.: 183B-416029-WO beta turn (β-turn) structures. In general, cyclization and D-amino acids may induce and / or stabilize beta-turns.

[0047] In some embodiments, the non-naturally occurring melanocortin agonist comprises a sequence according to Formula (I): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(I), wherein: X1is selected from the group consisting of norleucine (Nle), D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), tryptophan (Trp), and parafluoro-D-phenylalanine (p(F)dPhe); R4is selected from the group consisting of D-2’-naphthylalanine (dNal(2’)), p(F)dPhe, dPhe, His, Arg, and Trp; R5is selected from the group consisting of Arg, p(F)dPhe, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, Lys, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), dPhg, and p(F)dPhe; R7is absent or Trp; R8is selected from the group consisting of ornithine (Orn), 2,4-diaminobutyric acid (Dab), Asp, Dap, and Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: -13- 168588233.2Docket No.: 183B-416029-WO a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, a lactam bridge between R1and R8, when R1is Asp, R2is absent, R6is Lys or Ala, R7is Trp, R4is p(F)dPhe, and R8is Dab or Orn, a lactam bridge between R1and R8, when R1is Asp, R2and R7are absent, R4is dPhe or dNal(2’), and R8is Lys, and a lactam bridge between R1and R8, when R1is Glu, R2and R7are absent, R4is His or Arg and R8is Orn, provided that: when R4is dPhe, then X1is dAsp and X2-X3are absent, when R4is dNal(2’), then (i) X1is dAsp and X2is not dAla when X3is absent, (ii) X1is dOrn, X2is absent or dAla, and X3is absent (iii) X1is dPhe and X2is Gly or dAla, or (iv) X1is dPhg, X2is dAla, and X3is absent, when R4is p(F)dPhe, then (i) R5is Arg and R3and R6are not Arg, wherein when R6is Ala or dAla, then R8is Dab or Asp, when R6is Lys, then R8is Dab or Orn, and when R6is Dap, then R8is Dap, or (ii) R5is not Arg, wherein when R5is dPhe, then R8is not Dap, and when R4is Arg or His, then R5is not His, and R6is not Arg.

[0048] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein: X1is selected from the group consisting of norleucine (Nle), D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), tryptophan (Trp), and parafluoro-D-phenylalanine (p(F)dPhe); -14- 168588233.2Docket No.: 183B-416029-WO R4is selected from the group consisting of D-2’-naphthylalanine (dNal(2’)), p(F)dPhe, dPhe, His, Arg, and Trp; R5is selected from the group consisting of Arg, p(F)dPhe, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, Lys, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), dPhg, and p(F)dPhe; R7is absent or Trp; R8is selected from the group consisting of ornithine (Orn), 2,4-diaminobutyric acid (Dab), Asp, Dap, and Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, a lactam bridge between R1and R8, when R1is Asp, R2is absent, R6is Lys or Ala, R7is Trp, R4is p(F)dPhe, and R8is Dab or Orn, a lactam bridge between R1and R8, when R1is Asp, R2and R7are absent, R4is dPhe or dNal(2’), and R8is Lys, and a lactam bridge between R1and R8, when R1is Glu, R2and R7are absent, R4is His or Arg and R8is Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-dPhg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 2); Ac-dOrn-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-dOrn-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4); Ac-dAsp-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 5); -15- 168588233.2Docket No.: 183B-416029-WO Ac-dAsp-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 6); Ac-dPhg-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 7); Ac-dPhg-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); Ac-dPhe-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 9); Ac-dPhe-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 10); Ac-dOrn-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 11); Ac-dOrn-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 12); Ac-dAsp-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 13); Ac-dAsp-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 14); Ac-dPhg-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-dPhg-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-dPhe-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-dPhe-dAla-dAla-c[Asp-His-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: 19); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 20); Ac-Nle-c[Asp-dLys-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 21); Ac-Nle-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 22); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 23) Ac-Nle-c[Asp-His-dPhe-Asp-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 24); Ac-Nle-c[Asp-His-dPhe-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 25); Ac-Nle-c[Asp-His-dPhe-Ala-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 26); Ac-dOrn-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27); Ac-dOrn-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 28); Ac-dPhg-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 29); -16- 168588233.2Docket No.: 183B-416029-WO Ac-dAsp-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 30); Ac-dPhe-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 31); Ac-dPhg-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-dOrn-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 33); Ac-dPhg-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34); Ac-dPhg-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 35); Ac-Nle-c[Asp-Trp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 36); Ac-Nle-c[Asp-His-dNal(2')-Asp-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 37); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 40); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAla-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Dap-Trp-Dab]-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Dap-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Lys-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-His-Arg-p(F)dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[Asp-His-p(F)dPhe-dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 47); Ac-Nle-c[Asp-p(F)dPhe-Arg-His-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Nle-c[Glu-p(F)dPhe-Arg-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 49); and Ac-Nle-c[Asp-p(F)dPhe-His-Ala-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 50), wherein c represents cyclization through a lactam bond between R1and R8.

[0049] In some embodiments of the sequence of Formula (I), R2and R7are absent. In further embodiments, X1is not Nle, and one or more of X2-X3are optionally present. -17- 168588233.2Docket No.: 183B-416029-WO 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(IA) (SEQ ID NO: 51), wherein: X1is selected from the group consisting of D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent; R3is His; R4is D-2’-naphthylalanine (dNal(2’)) or dPhe; R5is Arg; R6is Trp; R7is absent; R8is lysine (Lys); Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between Asp at R1and Lys at R8, provided that: when R4is dPhe, then X1is dAsp and X2-X3are absent, when R4is dNal(2’), then (i) X1is dAsp and X2is not dAla when X3is absent, (ii) X1is dOrn, X2is absent or dAla, and X3is absent (iii) X1is dPhe and X2is Gly or dAla, or (iv) X1is dPhg, X2is dAla, and X3is absent.

[0050] 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(IA) (SEQ ID NO: 51), -18- 168588233.2Docket No.: 183B-416029-WO wherein: X1is selected from the group consisting of D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent; R3is His; R4is D-2’-naphthylalanine (dNal(2’)) or dPhe; R5is Arg; R6is Trp; R7is absent; R8is lysine (Lys); Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between Asp at R1and Lys at R8, provided that: when R4is dPhe, then X1is dAsp and X2-X3are absent, when R4is dNal(2’), then (i) X1is dAsp and X2is not dAla when X3is absent, (ii) X1is dOrn, X2is absent or dAla, and X3is absent (iii) X1is dPhe and X2is Gly or dAla, or (iv) X1is dPhg, X2is dAla, and X3is absent.

[0051] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA), wherein: X1is selected from the group consisting of D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; -19- 168588233.2Docket No.: 183B-416029-WO R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent; R3is His; R4is D-2’-naphthylalanine (dNal(2’)) or dPhe; R5is Arg; R6is Trp; R7is absent; R8is lysine (Lys); Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between Asp at R1and Lys at R8, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-dPhg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 2); Ac-dOrn-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-dOrn-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4); Ac-dAsp-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 5); Ac-dAsp-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 6); Ac-dPhg-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 7); Ac-dPhg-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); Ac-dPhe-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 9); Ac-dPhe-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 10); Ac-dOrn-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 11); Ac-dOrn-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 12); -20- 168588233.2Docket No.: 183B-416029-WO Ac-dAsp-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 13); Ac-dAsp-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 14); Ac-dPhg-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-dPhg-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-dPhe-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-dPhe-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 18); Ac-dOrn-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27); Ac-dOrn-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 28); Ac-dPhg-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 29); Ac-dAsp-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 30); Ac-dPhe-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 31); Ac-dPhg-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-dOrn-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 33); Ac-dPhg-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34); and Ac-dPhg-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 35), wherein c represents cyclization through a lactam bond between R1and R8.

[0052] In some embodiments of the sequence of Formula (I) or (IA), R4is dNal(2’). 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(IA(i)) (SEQ ID NO: 52), wherein: X1is selected from the group consisting of D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; -21- 168588233.2Docket No.: 183B-416029-WO R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent; R3is His; R4is D-2’-naphthylalanine (dNal(2’)); R5is Arg; R6is Trp; R7is absent; R8is lysine (Lys); Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between Asp at R1and Lys at R8, provided that: when X1is dAsp, then X2is not dAla when X3is absent, when X1is dOrn, then X2is absent or dAla, and X3is absent when X1is dPhe, then X2is Gly or dAla, and when X1is dPhg, then X2is dAla, and X3is absent.

[0053] 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(IA(i)) (SEQ ID NO: 52), wherein: X1is selected from the group consisting of D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent; -22- 168588233.2Docket No.: 183B-416029-WO R3is His; R4is D-2’-naphthylalanine (dNal(2’)); R5is Arg; R6is Trp; R7is absent; R8is lysine (Lys); Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between Asp at R1and Lys at R8, provided that: when X1is dAsp, then X2is not dAla when X3is absent, when X1is dOrn, then X2is absent or dAla, and X3is absent when X1is dPhe, then X2is Gly or dAla, and when X1is dPhg, then X2is dAla, and X3is absent.

[0054] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(i)), wherein: X1is selected from the group consisting of D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent; R3is His; R4is D-2’-naphthylalanine (dNal(2’)); R5is Arg; R6is Trp; R7is absent; -23- 168588233.2Docket No.: 183B-416029-WO R8is lysine (Lys); Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between Asp at R1and Lys at R8, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-dOrn-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27); Ac-dOrn-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 28); Ac-dPhg-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 29); Ac-dAsp-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 30); Ac-dPhe-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 31); Ac-dPhg-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-dOrn-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 33); Ac-dPhg-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34); and Ac-dPhg-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 35), wherein c represents cyclization through a lactam bond between R1and R8.

[0055] In some embodiments of the sequence of Formula (I), one of R2and R7is present. In further embodiments, X1is Nle, and X12X3are absent. Accordingly, in some embodiments, the sequence of Formula (I) is a sequence of Formula (IB): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(IB), wherein: X1is norleucine (Nle); R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); -24- 168588233.2Docket No.: 183B-416029-WO R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), tryptophan (Trp), and parafluoro-D-phenylalanine (p(F)dPhe); R4is selected from the group consisting of D-2’-naphthylalanine (dNal(2’)), p(F)dPhe, dPhe, His, Arg, and Trp; R5is selected from the group consisting of Arg, p(F)dPhe, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, Lys, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), dPhg, and p(F)dPhe; R7is absent or Trp; R8is selected from the group consisting of ornithine (Orn), 2,4-diaminobutyric acid (Dab), Asp, Dap, and Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, a lactam bridge between R1and R8, when R1is Asp, R2is absent, R6is Lys or Ala, R7is Trp, R4is p(F)dPhe, and R8is Dab or Orn, a lactam bridge between R1and R8, when R1is Glu, R2and R7are absent, R4is His or Arg and R8is Orn, provided that: when R4is p(F)dPhe, then (i) R5is Arg and R3and R6are not Arg, wherein when R6is Ala or dAla, then R8is Dab or Asp, when R6is Lys, then R8is Dab or Orn, and when R6is Dap, then R8is Dap, or (ii) R5is not Arg, wherein when R5is dPhe, then R8is not Dap, and when R4is Arg or His, then R5is not His, and R6is not Arg. -25- 168588233.2Docket No.: 183B-416029-WO

[0056] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(IB), wherein: X1is norleucine (Nle); R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), tryptophan (Trp), and parafluoro-D-phenylalanine (p(F)dPhe); R4is selected from the group consisting of D-2’-naphthylalanine (dNal(2’)), p(F)dPhe, dPhe, His, Arg, and Trp; R5is selected from the group consisting of Arg, p(F)dPhe, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, Lys, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), dPhg, and p(F)dPhe; R7is absent or Trp; R8is selected from the group consisting of ornithine (Orn), 2,4-diaminobutyric acid (Dab), Asp, Dap, and Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, a lactam bridge between R1and R8, when R1is Asp, R2is absent, R6is Lys or Ala, R7is Trp, R4is p(F)dPhe, and R8is Dab or Orn, -26- 168588233.2Docket No.: 183B-416029-WO a lactam bridge between R1and R8, when R1is Glu, R2and R7are absent, R4is His or Arg and R8is Orn, provided that: when R4is p(F)dPhe, then (i) R5is Arg and R3and R6are not Arg, wherein when R6is Ala or dAla, then R8is Dab or Asp, when R6is Lys, then R8is Dab or Orn, and when R6is Dap, then R8is Dap, or (ii) R5is not Arg, wherein when R5is dPhe, then R8is not Dap, and when R4is Arg or His, then R5is not His, and R6is not Arg.

[0057] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB), wherein: X1is norleucine (Nle); R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), tryptophan (Trp), and parafluoro-D-phenylalanine (p(F)dPhe); R4is selected from the group consisting of D-2’-naphthylalanine (dNal(2’)), p(F)dPhe, dPhe, His, Arg, and Trp; R5is selected from the group consisting of Arg, p(F)dPhe, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, Lys, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), dPhg, and p(F)dPhe; R7is absent or Trp; R8is selected from the group consisting of ornithine (Orn), 2,4-diaminobutyric acid (Dab), Asp, Dap, and Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and -27- 168588233.2Docket No.: 183B-416029-WO the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, a lactam bridge between R1and R8, when R1is Asp, R2is absent, R6is Lys or Ala, R7is Trp, R4is p(F)dPhe, and R8is Dab or Orn, a lactam bridge between R1and R8, when R1is Glu, R2and R7are absent, R4is His or Arg and R8is Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 40); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAla-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Dap-Trp-Dab]-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Dap-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Lys-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-His-Arg-p(F)dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[Asp-His-p(F)dPhe-dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 47); Ac-Nle-c[Asp-p(F)dPhe-Arg-His-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Nle-c[Glu-p(F)dPhe-Arg-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 49); and Ac-Nle-c[Asp-p(F)dPhe-His-Ala-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 50), wherein c represents cyclization through a lactam bond between R1and R8.

[0058] In some embodiments of the sequence of Formula (I) or (IB), the non-naturally occurring melanocortin analog is cyclized between Asp or Dap at R1and Dap or Asp at R8. -28- 168588233.2Docket No.: 183B-416029-WO Accordingly, in some embodiments, the sequence of Formula (I) or (IB) is a sequence of Formula (IB(i)): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(IB(i)), wherein: X1is norleucine (Nle); R1is aspartic acid (Asp) or 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), and parafluoro-D-phenylalanine (p(F)dPhe); R4is p(F)dPhe or Arg; R5is selected from the group consisting of Arg, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), and dPhg; R7is absent or Trp; R8is Dap or Asp; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, provided that: when R4is p(F)dPhe, then (i) R5is Arg and R3and R6are not Arg, wherein when R6is Ala or dAla, then R8is Asp and when R6is Dap, then R8is Dap, or (ii) R5is not Arg, wherein when R5is dPhe, then R8is not Dap, and when R4is Arg, then R5is not His.

[0059] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB(i)): -29- 168588233.2Docket No.: 183B-416029-WO X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(IB(i)), wherein: X1is norleucine (Nle); R1is aspartic acid (Asp) or 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), and parafluoro-D-phenylalanine (p(F)dPhe); R4is p(F)dPhe or Arg; R5is selected from the group consisting of Arg, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), and dPhg; R7is absent or Trp; R8is Dap or Asp; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, provided that: when R4is p(F)dPhe, then (i) R5is Arg and R3and R6are not Arg, wherein when R6is Ala or dAla, then R8is Asp and when R6is Dap, then R8is Dap, or (ii) R5is not Arg, wherein when R5is dPhe, then R8is not Dap, and when R4is Arg, then R5is not His.

[0060] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB(i)), wherein: X1is norleucine (Nle); R1is aspartic acid (Asp) or 2,3-diaminopropionic acid (Dap); -30- 168588233.2Docket No.: 183B-416029-WO R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), and parafluoro-D-phenylalanine (p(F)dPhe); R4is p(F)dPhe or Arg; R5is selected from the group consisting of Arg, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), and dPhg; R7is absent or Trp; R8is Dap or Asp; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAla-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Dap-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Lys-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-His-Arg-p(F)dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[Asp-His-p(F)dPhe-dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 47); and Ac-Nle-c[Asp-p(F)dPhe-Arg-His-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 48), -31- 168588233.2Docket No.: 183B-416029-WO wherein c represents cyclization through a lactam bond between R1and R8.

[0061] In some embodiments of the sequence of any one of Formulae (I), (IB) and (IB(i)), R2is absent and R7is present. Accordingly, in some embodiments, the sequence of Formula (I) or (IB) is a sequence of Formula (IB(ii)): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(IB(ii)) (SEQ ID NO: 53), wherein: X1is norleucine (Nle); R1is aspartic acid (Asp); R2is absent; R3is His; R4is para-fluoro-D-phenylalanine (p(F)dPhe); R5is selected from the group consisting of His, arginine (Arg), β-glycine (β-Gly), D- aspartic acid (dAsp), D-alanine (dAla), alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), 2,3-diaminopropionic acid (Dap), lysine (Lys), D-lysine (dLys), leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Ala, dAla, Arg, His, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), and dPhg; R7is Trp; R8is Dap; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R1and Dap at R8, provided that: when R5is Arg, then R6is not Arg, wherein when R6is Ala or dAla, then R8is Asp and when R6is Dap, then R8is Dap, and when R5is dPhe, then R8is not Dap.

[0062] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB(ii)): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(IB(ii)) (SEQ ID NO: 53), -32- 168588233.2Docket No.: 183B-416029-WO wherein: X1is norleucine (Nle); R1is aspartic acid (Asp); R2is absent; R3is His; R4is para-fluoro-D-phenylalanine (p(F)dPhe); R5is selected from the group consisting of His, arginine (Arg), β-glycine (β-Gly), D- aspartic acid (dAsp), D-alanine (dAla), alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), 2,3-diaminopropionic acid (Dap), lysine (Lys), D-lysine (dLys), leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Ala, dAla, Arg, His, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), and dPhg; R7is Trp; R8is Dap; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R1and Dap at R8, provided that: when R5is Arg, then R6is not Arg, wherein when R6is Ala or dAla, then R8is Asp and when R6is Dap, then R8is Dap, and when R5is dPhe, then R8is not Dap.

[0063] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB(ii)), wherein: X1is norleucine (Nle); R1is aspartic acid (Asp); R2is absent; R3is His; R4is para-fluoro-D-phenylalanine (p(F)dPhe); -33- 168588233.2Docket No.: 183B-416029-WO R5is selected from the group consisting of His, arginine (Arg), β-glycine (β-Gly), D- aspartic acid (dAsp), D-alanine (dAla), alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), 2,3-diaminopropionic acid (Dap), lysine (Lys), D-lysine (dLys), leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Ala, dAla, Arg, His, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), and dPhg; R7is Trp; R8is Dap; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R1and Dap at R8, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAla-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Dap-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Lys-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); and Ac-Nle-c[Asp-His-p(F)dPhe-dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 47), wherein c represents cyclization through a lactam bond between R1and R8.

[0064] In some embodiments, the non-naturally occurring melanocortin analog has one or more beta hairpin (β-hairpin) and / or beta turn (β-turn) structures. In some embodiments, R2or R3of the sequence according to any one of Formula (I)-(IB(ii)) provides the β-hairpin and / or β-turn structures of the melanocortin analog.

[0065] As will be appreciated by the skilled artisan, non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (I)-(IC), have an N- -34- 168588233.2Docket No.: 183B-416029-WO 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 (I)-(I IB(ii)) may be at any one of X1, X2, or X3. Similarly, the C-terminus of a non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (I)-(IB(ii)) may be at Y2.

[0066] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group. In some embodiments, the acyl group is acetyl ).

[0067] Alternatively,N-terminus of the non-naturally occurring melanocortin analog, if present, is not modified.

[0068] The moiety Y1Y2Y3Y4represents a C-terminus of the non-naturally occurring melanocortin analog. In some embodiments, the most C-terminal residues of the melanocortin analog are dVal-dPro. The C-terminal dVal-dPro moiety may confer improved properties on the melanocortin analog, such as increased plasma duration and improved transport across the blood-brain-barrier, the epithelium, and / or gastrointestinal tract

[0069] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified an amide In the sequence of any one of Formula (I)-(IB(ii)), a non-analog with a C- terminus modified by an amide may be represented by a terminal -NH2;.

[0070] In some embodiments of any one of Formula (I)-(IB(ii)), the C-terminus of the non-naturally occurring melanocortin analog is not modified. In the sequence of any one of Formula (I)-(IB(ii)), a non-naturally occurring melanocortin analog with an unmodified C- terminus may be represented by -OH. -35- 168588233.2Docket No.: 183B-416029-WO

[0071] Non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (I)-(IB(ii)) may be cyclized. For example, the non-naturally occurring melanocortin analog may be cyclized through a moiety selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, a lactam bridge between R1and R8, when R1is Asp, R2is absent, R6is Lys or Ala, R7is Trp, R4is p(F)dPhe, and R8is Dab or Orn, a lactam bridge between R1and R8, when R1is Asp, R2and R7are absent, R4is dPhe or dNal(2’), and R8is Lys, and a lactam bridge between R1and R8, when R1is Glu, R2and R7are absent, R4is His or Arg and R8is Orn.

[0072] Non-naturally occurring melanocortin analogs of the present technology may have an expanded cycle. In some embodiments, a spacer amino acid is inserted within a cyclic portion of the melanocortin analog. The spacer amino acid may be inserted before or after the R4position of the melanocortin analog. Accordingly, in the non-naturally occurring melanocortin analogs of any one of Formula (I)-(IB(ii)) at least one of R2and R7is present.

[0073] In some embodiments, X1is Nle. In further embodiments, R4is p(F)dPhe. In some embodiments, the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Asp at R1and Dap, Orn, or Dab at R8. In further embodiments, In some embodiments, the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Asp at R1and Dap at R8. Alternatively, in some embodiments, the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Dap at R1and Asp at R8.

[0074] In some embodiments, the spacer amino acid is present before the R4position of the melanocortin analog. In such embodiments, R2is present and R7is absent.

[0075] In some embodiments, R2is His and R3is a spacer amino acid. Spacer amino acids may be used to expand the cycle of the melanocortin analogs without effecting binding activity or potency at the melanocortin 1 receptor. Melanocortin analogs with expanded cycles may have improve stability and / or decreased activity on the melanocortin 1 receptor. -36- 168588233.2Docket No.: 183B-416029-WO

[0076] The spacer amino acid at R3may be an aliphatic or basic spacer amino acid. In some embodiments, R2is β-Gly or dLys. In further embodiments, the sequence of any one of Formula (I)-(IB(ii)) is: Ac-Nle-c[Asp-His-β-Gly-p(F)dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 54); or Ac-Nle-c[Dap-His-dLys-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 55), wherein c represents cyclization between R1and R8via a lactam bond.

[0077] In some embodiments, the spacer amino acid is present after the R4position of the melanocortin analog. In such embodiments, R2is absent and R7is present. In some embodiments, R2is absent and any one of R5-R7is a spacer amino acid.

[0078] In some embodiments, R5is a spacer amino acid, R6is Arg, and R7is Trp.

[0079] The spacer amino acid at R5may be an basic spacer amino acid. In some embodiments, R5is selected from Dap, Lys, and dLys. In further embodiments, the non- naturally occurring melanocortin analog is cyclized via a lactam bond between Dap at R1and Asp at R8. In some embodiments, the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-Nle-c[Dap-His-p(F)dPhe-Dap-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-Nle-c[Dap-His-p(F)dPhe-Lys-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 57); and Ac-Nle-c[Dap-His-p(F)dPhe-dLys-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 58), wherein c represents cyclization between R1and R8via a lactam bond.

[0080] The spacer amino acid at R5may also be an aliphatic, aromatic, or negatively charged spacer amino acid. In some embodiments, R5is selected from Ala, dAla, β-Gly, Ser, dSer, Phe, Leu, dAsp, and dPhg. In further embodiments, the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Asp at R1and Dap at R8. In some embodiments, the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Ala-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 59); Ac-Nle-c[Asp-His-p(F)dPhe-dAla-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 60); Ac-Nle-c[Asp-His-p(F)dPhe-β-Gly-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 61); -37- 168588233.2Docket No.: 183B-416029-WO Ac-Nle-c[Asp-His-p(F)dPhe-Ser-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Asp-His-p(F)dPhe-dSer-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c[Asp-His-p(F)dPhe-Phe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 64); Ac-Nle-c[Asp-His-p(F)dPhe-Leu-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 65); Ac-Nle-c[Asp-His-p(F)dPhe-dAsp-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 66); and Ac-Nle-c[Asp-His-p(F)dPhe-dPhg-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 67), wherein c represents cyclization between R1and R8via a lactam bond.

[0081] Alternatively, in some embodiments, R5is selected from Ala, dAla, Phe, and dPhe, and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Dap at R1and Asp at R8. In some embodiments, the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-Nle-c[Dap-His-p(F)dPhe-Ala-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Dap-His-p(F)dPhe-dAla-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Nle-c[Dap-His-p(F)dPhe-Phe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 70); and Ac-Nle-c[Dap-His-p(F)dPhe-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 71), wherein c represents cyclization between R1and R8via a lactam bond.

[0082] In some embodiments, R5is Arg, R6is a spacer amino acid, and R7is Trp.

[0083] The spacer amino acid at R6may be a basic spacer amino acid. In some embodiments, R6is selected from Dap, dOrn, Lys, and dLys. In further embodiments, the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Dap or Asp at R1and Asp, Dab, Orn, or Dap at R8. In some embodiments, the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Dap-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dOrn-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dLys-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 75); -38- 168588233.2Docket No.: 183B-416029-WO Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dab]-dVal-dPro-NH2 (SEQ ID NO: 76); and Ac-Nle-c[Dap-His-p(F)dPhe-Arg-dLys-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 77), wherein c represents cyclization between R1and R8via a lactam bond.

[0084] The spacer amino acid at R6may also be an aliphatic, aromatic, acidic, or polar spacer amino acid. In some embodiments, R6is selected from Ala, Ser, dSer, Leu, dLeu, Asp, dAsp, Phg, and dPhg. In further embodiments, the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Asp at R1and Dap at R8. In some embodiments, the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dab]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ser-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dSer-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Leu-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 81); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dLeu-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Asp-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 83); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAsp-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Phg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dPhg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 86); wherein c represents cyclization between R1and R8via a lactam bond.

[0085] Alternatively, in some embodiments, R6is Ala or dAla, and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Dap at R1and Asp at R8. In some embodiments, the sequence of any one of Formula (I)-(IB(ii)) is Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Ala-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 87); or Ac-Nle-c[Dap-His-p(F)dPhe-Arg-dAla-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 88), wherein c represents cyclization between R1and R8via a lactam bond. -39- 168588233.2Docket No.: 183B-416029-WO

[0086] In some embodiments, R2is absent, R7is present, and the non-naturally occurring melanocortin analog comprises an alanine spacer. In some embodiments, R5or R6is Ala. In further embodiments, the remaining positions in the melanocortin cycle are each independently one of His, p(F)dPhe, Arg, and Trp. In some embodiments, the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-Nle-c[Asp-Arg-p(F)dPhe-His-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 89); Ac-Nle-c[Asp-p(F)dPhe-Arg-Ala-His-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 90); and Ac-Nle-c[Asp-Arg-p(F)dPhe-Ala-His-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 91), wherein c represents cyclization between R1and R8via a lactam bond.

[0087] In some embodiments, R2and R7are absent. In further embodiments, the non- naturally occurring melanocortin analog is cyclized through a lactam bond between Glu at R1and Orn at R8. In some embodiments, the sequence of any one of Formula (I)-(IB(ii)) is: Ac-Nle-c[Glu-p(F)dPhe-His-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 92); and Ac-Nle-c[Glu-His-Trp-Arg-p(F)dPhe-Orn]-dVal-dPro-NH2 (SEQ ID NO: 93), wherein c represents cyclization between R1and R8via a lactam bond.

[0088] In some embodiments, R2and R7are absent, and X1is not Nle. In some embodiments, the non-naturally occurring melanocortin comprises a sequence of any one of Formula (I)-(IB(ii)), wherein the N-terminus comprises a charged residue. In some embodiments, the non-naturally occurring melanocortin comprises a sequence of any one of Formula (I)-(IB(ii)), wherein the N-terminus comprises an aromatic residue. In some embodiments, the non-naturally occurring melanocortin comprises a sequence of any one of Formula (I)-(IB(ii)), wherein the N-terminus is extended. Such N-termini may confer stabilizing properties on the melanocortin analogs of the present technology.

[0089] In some embodiments, the melanocortin analog is cyclized through a lactam bond between Asp at R1and Lys at R8. In further embodiments, R4is dNal(2’). In still further embodiments, X1is selected from the group consisting of dAsp, dOrn, dPhe, and dPhg. In some embodiments, one or both of X2and X3are present. Alternatively, in some embodiments, X2and X3are absent. In some embodiments, the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: -40- 168588233.2Docket No.: 183B-416029-WO Ac-dOrn-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 94); Ac-dAsp-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 95); Ac-dOrn-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 96); Ac-dAsp-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 97); Ac-dPhg-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 98); Ac-dPhe-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 99); Ac-dPhe-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-dAsp-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 101); Ac-dAsp-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102); Ac-dPhe-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 103); and Ac-dPhe-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 104), wherein c represents cyclization between R1and R8via a lactam bond.

[0090] In some embodiments, the melanocortin analog is cyclized through a lactam bond between Asp at R1and Lys at R8and R4is dPhe. In further embodiments, X1is dAsp. In some embodiments, the sequence of any one of Formula (I)-(IB(ii)) is: Ac-dAsp-c[Asp- His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 105), wherein c represents cyclization between R1and R8via a lactam bond.

[0091] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence selected from any one of SEQ ID NOs: 54-105. Non-Naturally Occurring Melanocortin Analog Synthesis

[0092] The melanocortin analogs described herein 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 -41- 168588233.2Docket No.: 183B-416029-WO reactive groups protected. In an exemplary procedure, the peptides described herein 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 described herein.

[0093] 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.

[0094] Solid phase peptide synthesis methods are well known and practiced in the art. In such methods, the synthesis of peptides can 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).

[0095] 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.

[0096] 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, -42- 168588233.2Docket No.: 183B-416029-WO such as t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc is useful for alpha amino protection.

[0097] 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.

[0098] 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)-α-[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.

[0099] 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 protecting groups may be removed using methods well known in the art for further derivatization of the peptide.

[0100] 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 -43- 168588233.2Docket No.: 183B-416029-WO groups present on the peptide will be determined, in part, by the characteristics that are desired in the peptide.

[0101] 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) or 1-methyl-2-pyrrolidone (NMP). Suitable cyclic coupling reagents include, for example, 2-(1H-benzotriazol-1-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-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-1H-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 (DCCl / HOBt). Coupling is convention initiated by use of a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N-methylmorpholine (NMM).

[0102] Following cleavage of peptides from the solid phase following their synthesis, the peptide can 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, can also be employed. Once purified, the peptide can 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

[0103] The melanocortin analog peptides described herein 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 -44- 168588233.2Docket No.: 183B-416029-WO 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.

[0104] When the peptides described herein 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 described herein 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 described herein 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. Pharmaceutical Compositions

[0105] Pharmaceutical compositions comprising the carriers and / or excipients disclosed in the present technology facilitate delivery of the non-naturally occurring melanocortin analog disclosed herein in any of its embodiments to a subject.

[0106] In some embodiments, the non-naturally occurring melanocortin analog is present in a pharmaceutical composition in a therapeutically effective amount. The therapeutically effective amount may be an amount sufficient to elicit a desired response in the subject, such as, for example, weight loss. -45- 168588233.2Docket No.: 183B-416029-WO

[0107] In some embodiments, the non-naturally occurring melanocortin analog is present in the 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 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 composition in a concentration of 5 mg / mL to 100 mg / mL, or about 50 mg / mL, relative to a total volume of the composition.

[0108] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of Formula (I)-(IB(ii)) and the non-naturally occurring melanocortin analog is present in the composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the composition. For example, the non-naturally occurring melanocortin analog comprising a sequence of any one of Formula (I)-(IB(ii)) is present in the 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 composition. In some embodiments, the non-naturally occurring melanocortin analog comprising a sequence of of any one of Formula (I)-(IB(ii)) is present in the composition in a concentration of about 50 mg / mL, relative to a total volume of the composition.

[0109] In some embodiments, the pharmaceutical composition comprising the non- naturally occurring melanocortin analog is formulated for intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration. In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally. In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously. In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject orally.

[0110] Pharmaceutical compositions disclosed herein formulated for parenteral administration may be in the form of an aqueous or non-aqueous isotonic sterile injection -46- 168588233.2Docket No.: 183B-416029-WO solution or suspension. The term “parenteral”, as used herein, includes subcutaneous, intravenous, intraperitoneal, intramuscular, and intralesional, or infusion techniques. Pharmaceutical compositions disclosed herein formulated for oral administration may be in the form of tablet, capsule, lozenge, pill, sachet, or any other orally deliverable form know in the art.

[0111] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) 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 even 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 a sequence of any one of Formula (I)-(IB(ii)).

[0112] In some embodiments, the non-naturally occurring melanocortin analog crosses blood-brain-barrier (BBB) of the subject.

[0113] 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.

[0114] The pharmaceutical composition comprising the carriers and / or excipients disclosed in the present technology facilitate delivery (e.g., parenteral administration, in particular subcutaneous injection) of the non-naturally occurring melanocortin analog disclosed herein in any of its embodiments to a subject. Other purposes of the compositions comprising the carriers and / or excipients are to enhance dispersion, solubility, and stability of the non-naturally occurring melanocortin analog, and to reduce adverse injection site reactions. -47- 168588233.2Docket No.: 183B-416029-WO

[0115] The carriers and / or excipients of the pharmaceutical composition can generally include one or more of the following components: a pH buffered aqueous solution comprising (a) sodium acetate, (b) Tris, and (c) water. In some embodiments, all components are compatible with 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.

[0116] In some embodiments, the carrier and / or excipient is isotonic.

[0117] In order to achieve a desirable tonicity, the composition of the present technology can further include a salt such as sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride. In some embodiments, the salt is present in the composition in a concentration of 0.1 mg / mL to 50 mg / mL, 1 mg / mL to 25 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0118] The carriers and / or excipients of the composition may also include a pH buffered aqueous solution which comprises (a) sodium acetate, (b) Tris, and (c) water.

[0119] The water used herein can 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.

[0120] In some embodiments, the pharmaceutical composition further 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.

[0121] 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 is present in the 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. In some embodiments, sodium acetate is present in the -48- 168588233.2Docket No.: 183B-416029-WO 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 is present in the 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.

[0122] In some embodiments, sodium acetate is present in the composition in a molar concentration of 5 mM to 700 mM, relative to a total volume of the composition. For example, sodium acetate is present in the 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. In some embodiments, sodium acetate is present in the 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 is present in the 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.

[0123] The term “Tris” represents tris(hydroxymethyl)aminomethane 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 composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, Tris is present in the 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. In some embodiments, Tris is present in the 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 is present in the 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.

[0124] In some embodiments, Tris is present in the composition in a molar concentration of 2 mM to 500 mM, relative to a total volume of the composition. For example, Tris is present in the 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. In some -49- 168588233.2Docket No.: 183B-416029-WO embodiments, Tris is present in the composition in a molar concentration of about 50 mM to about 70 mM, relative to a total volume of the composition. For example, Tris is present in the 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.

[0125] In some embodiments, the pH buffered aqueous solution provides the 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.

[0126] In addition to sodium acetate and Tris, the composition may further 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 composition comprises acetic acid as an additional buffering agent.

[0127] In some embodiments, a weight ratio of sodium acetate to Tris is 1:4 to 4:1, 2:7 to 7:2, 1:3 to 3:1, 2:5 to 5:2, 1:2 to 2:1, 2:3 to 3:2, or about 1:1. In some embodiments, the weight ratio of sodium acetate to Tris is about 1:1.

[0128] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is 1:1 to 20:1, 3:2 to 15:1, 2:1 to 12:1, 3:1 to 10:1, 4:1 to 9:1, 5:1 to 8:1, or 6:1 to 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is about 7:1.

[0129] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is 1:1 to 20:1, 3:2 to 15:1, 2:1 to 12:1, 3:1 to 10:1, 4:1 to 9:1, 5:1 to 8:1, or 6:1 to 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is about 7:1.

[0130] 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, -50- 168588233.2Docket No.: 183B-416029-WO 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.

[0131] If present, the concentration of the preservative agent can range from 0.001 mg / mL to 50 mg / mL, 0.01 mg / mL to 25 mg / mL, 0.1 mg / mL to 10 mg / mL, or 1 mg / mL to 5 mg / mL, relative to a total volume of the composition.

[0132] In some embodiments, the composition is in the form of an aqueous solution or a suspension. In some embodiments, the composition is in the form of an emulsion. In some embodiments, the composition is in the form of an aqueous solution. In some embodiments, the composition is in the form of an aqueous solution which is clear, colorless, and / or free of visible foreign matter.

[0133] The active ingredient(s) (e.g., the non-naturally occurring melanocortin analog) may be dissolved or suspended in the aforementioned 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.

[0134] In some embodiments, the composition has a pH ranging from 6.5 to 8.5. In some embodiments, the 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.

[0135] In some embodiments, the 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 composition has a pH ranging from about 7.3 to about 7.4. In some embodiments, the composition has a pH of 7.3 or 7.4.

[0136] In some embodiments, the composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the composition has 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 composition has an osmolarity of about 250 mOsm / kg, -51- 168588233.2Docket No.: 183B-416029-WO 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 composition has an osmolality ranging from about 275 mOsm / kg to about 330 mOsm / kg. In some embodiments, the composition has an osmolality of about 279 mOsm / kg, about 314 mOsm / kg, or about 329 mOsm / kg.

[0137] In some embodiments, the composition has a viscosity ranging from 0.5 cP to 5 cP. For example, the composition has a viscosity ranging from 0.5 cP to 5 cP, 0.75 cP to 4.5 cP, 1.0 cP to 4 cP, 1.2 cP to 3.5 cP, 1.3 cP to 3 cP, 1.4 cP to 2.5 cP, 1.5 cP to 2 cP, or 1.6 cP to 1.8 cP. In some embodiments, the composition has a viscosity of 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 composition has a viscosity of about 1.4 cP or 1.6 cP.

[0138] In some embodiments, the pharmaceutical composition further 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.

[0139] In some embodiments, the pharmaceutical composition further comprises a surfactant, such as a sorbitan ester.

[0140] In some embodiments, the pharmaceutical composition further comprises a flavoring or scent, such as an aromatic oil. Use of non-naturally occurring melanocortin analogs

[0141] The non-naturally occurring melanocortin analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions including the non-naturally occurring melanocortin analogs described herein are useful to treat, reduce, or prevent conditions associated with agonizing MC1R. The non-naturally occurring melanocortin analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions including the non-naturally occurring melanocortin analogs described herein are also useful to stimulate appetite, increase body weight and / or increase food consumption. Examples of conditions -52- 168588233.2Docket No.: 183B-416029-WO associated with agonizing MC1R include, but are not limited to, psychological diseases and conditions, allergies, intolerances, gastrointestinal diseases and conditions, side-effects from a medication, substance abuse, viral infections, bacterial infections, food poisoning, dehydration, fatigue, hormonal imbalances, pain, cardiovascular diseases and conditions, anemia, autoimmune diseases and conditions, respiratory diseases and conditions, and inflammatory diseases and conditions. Dosing and Administration

[0142] The non-naturally occurring melanocortin analog may be formulated for delivery to a subject in need thereof. In some embodiments, the non-naturally occurring melanocortin analog is formulated for intraperitoneal, intravenous, parenteral, depot, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration. In some embodiments, the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is formulated for subcutaneous administration. In some embodiments, the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is formulated for oral administration. In some embodiments, the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is formulated for depot administration.

[0143] In some embodiments, the non-naturally occurring melanocortin receptor agonist is administered at a dose of about 0.001 mg / kg to about 1000 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin receptor agonist is administered at a dose of about 10 mg / kg to about 250 mg / kg per body weight of the subject once daily. In some embodiments, non-naturally occurring melanocortin receptor agonist is administered at a dose of about 15 mg / kg to about 100 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin receptor agonist is administered at a dose of about 20 mg / kg to about 75 mg / kg per body weight of the subject once daily.

[0144] In some embodiments, the non-naturally occurring melanocortin receptor agonist is administered at a dose of about 0.001 mg / kg to about 25 mg / kg per body weight of the subject. In some embodiments, the non-naturally occurring melanocortin receptor agonist is administered at a dose of about 0.5 mg / kg to about 10 mg / kg per body weight of -53- 168588233.2Docket No.: 183B-416029-WO the subject. In some embodiments, the amount administered is a therapeutically effective amount.

[0145] In some embodiments, the non-naturally occurring melanocortin receptor agonist is administered at a dose of about 0.001 mg / kg, about 0.01 mg / kg, about 0.10 mg.kg, about 0.5 mg / kg, about 1.0 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 50 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 400 mg / kg, about 450 mg / kg, or about 500 mg / kg per body weight of the subject once daily or twice daily.

[0146] In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject for at least about 1 day, about 1 week, about 1 month, about 3 months, about 6 months, about 1 year, or about 5 years.

[0147] In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject for at least about 1 day, about 5 days, about 7 days, about 14 days, about 21 days, about 28 days, about 35 days, about 40 days, about 45 days, about 50 days, about 60 days, about 75 days, about 90 days, about 100 days, about 110 days, or about 120 days. EXAMPLES

[0148] 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. -54- 168588233.2Docket No.: 183B-416029-WO Example 1: Peptide Synthesis-Generic

[0149] The non-naturally occurring melanocortin analogs described herein 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 solid-phase synthesis utilized a variety of resins and reagents and may involve additional purification steps.

[0150] 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.

[0151] 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.

[0152] 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 -55- 168588233.2Docket No.: 183B-416029-WO its electrophilicity. Some methods of coupling rely on the formation 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-chlorotrityl chloride resin via an ester linkage. Some methods of coupling rely on the formation of an aminde 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)-α-[1-(9H-fluor-en-9-yl)-methoxyformamido]-2,4-dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) via an amide linkage.

[0153] 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

[0154] 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.

[0155] 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- -56- 168588233.2Docket No.: 183B-416029-WO 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.

[0156] 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

[0157] 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.

[0158] 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-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H- 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-1H-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- -57- 168588233.2Docket No.: 183B-416029-WO hydroxybenzotriazole (DCCl / 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

[0159] The agonist and antagonist activity of exemplary non-naturally occurring melanocortin analogs at the melanocortin receptors (e.g., MC1R, 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

[0160] Compounds were delivered as powder (1 mg) or 10 mM solutions (100 μl) 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 lines Receptor Cell Line Reference agonist Reference antagonist MC1R CHO-K1 NDP-α-MSH N / A MC3R CHO-K1 NDP-α-MSH SHU9119 MC4R CHO-K1 NDP-α-MSH SHU9119 MC5R CHO-K1 NDP-α-MSH N / A Compound Testing

[0161] 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. -58- 168588233.2Docket No.: 183B-416029-WO Testing Protocol

[0162] Cyclic AMP (cAMP) Homogenous Time-Resolved Fluorescence (HTRF) assay for Gs coupled receptor:

[0163] 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 KCl, 1.25 mM MgSO4, 124 mM NaCl, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH2PO4, 1.45 mM CaCl2, 0.5 g / l BSA, supplemented with 1mM IBMX or 25μM Rolipram).

[0164] Dose response curves were performed in parallel with the reference compounds.

[0165] For agonist test (384well): 5 μl of cells were mixed with 5 μl 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. Reference agonist NDP-α- MSH was also tested as a comparator.

[0166] For antagonist test (384well): 5 μl of cells were mixed in the wells of an assay plate with 5 μl of a mix of the test compound at increasing concentrations 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. Reference antagonist SHU9119 was also tested as a comparator. Quality Control for Compound Testing

[0167] 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. -59- 168588233.2Docket No.: 183B-416029-WO

[0168] Reference values thus obtained for the test were compared to historical values obtained from the same receptor and used to validate the experimental session.

[0169] 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.

[0170] 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

[0171] Group A included non-naturally occurring melanocortin analogs A1 to A25, all of which are cyclic peptides comprising the motif His-p(F)dPhe-Arg-Trp (SEQ ID NO: 106), or a derivative thereof. Derivatives of SEQ ID NO: 106 may include insertions between His and p(F)dPhe, insertions between p(F)dPhe and Arg, or insertions between Arg and Trp. The residues inserted at such positions may be aliphatic, aromatic, or acidic spacer amino acids. Group A melanocortin analogs also comprise Nle at the N-terminus and dVal-dPro at the C-terminus. Group A non-naturally occurring melanocortin analogs are provided in Table 2. Table 2. Non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO A1107Ac-Nle-c[Asp-His-bGly-p(F)dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 A259Ac-Nle-c[Asp-His-p(F)dPhe-Ala-Arg-Trp-Dap]-dVal-dPro-NH2 A360Ac-Nle-c[Asp-His-p(F)dPhe-dAla-Arg-Trp-Dap]-dVal-dPro-NH2 A4108Ac-Nle-c[Asp-His-p(F)dPhe-bGly-Arg-Trp-Dap]-dVal-dPro-NH2 A562Ac-Nle-c[Asp-His-p(F)dPhe-Ser-Arg-Trp-Dap]-dVal-dPro-NH2 A663Ac-Nle-c[Asp-His-p(F)dPhe-dSer-Arg-Trp-Dap]-dVal-dPro-NH2 A764Ac-Nle-c[Asp-His-p(F)dPhe-Phe-Arg-Trp-Dap]-dVal-dPro-NH2 A865Ac-Nle-c[Asp-His-p(F)dPhe-Leu-Arg-Trp-Dap]-dVal-dPro-NH2 A966Ac-Nle-c[Asp-His-p(F)dPhe-dAsp-Arg-Trp-Dap]-dVal-dPro-NH2 A1067Ac-Nle-c[Asp-His-p(F)dPhe-dPhg-Arg-Trp-Dap]-dVal-dPro-NH2 A1179Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ser-Trp-Dap]-dVal-dPro-NH2 A1280Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dSer-Trp-Dap]-dVal-dPro-NH2 A1381Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Leu-Trp-Dap]-dVal-dPro-NH2 A1482Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dLeu-Trp-Dap]-dVal-dPro-NH2 A1583Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Asp-Trp-Dap]-dVal-dPro-NH2 -60- 168588233.2Docket No.: 183B-416029-WO A1684Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAsp-Trp-Dap]-dVal-dPro-NH2 A1785Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Phg-Trp-Dap]-dVal-dPro-NH2 A1886Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dPhg-Trp-Dap]-dVal-dPro-NH2 A1968Ac-Nle-c[Dap-His-p(F)dPhe-Ala-Arg-Trp-Asp]-dVal-dPro-NH2 A2069Ac-Nle-c[Dap-His-p(F)dPhe-dAla-Arg-Trp-Asp]-dVal-dPro-NH2 A2170Ac-Nle-c[Dap-His-p(F)dPhe-Phe-Arg-Trp-Asp]-dVal-dPro-NH2 A22 Ac-Nle-c[Dap-His-p(F)dPhe-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 A23 Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Ala-Trp-Asp]-dVal-dPro-NH2 A24 Ac-Nle-c[Dap-His-p(F)dPhe-Arg-dAla-Trp-Asp]-dVal-dPro-NH2 A25 Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dab]-dVal-dPro-NH2

[0172] Group B included non-naturally occurring melanocortin analogs B1 to B10, all of which are cyclic peptides comprising the motif His-p(F)dPhe-Arg-Trp (SEQ ID NO: 106), or a derivative thereof. Derivatives of SEQ ID NO: 106 may include insertions between His and p(F)dPhe, insertions between p(F)dPhe and Arg, or insertions between Arg and Trp. The residues inserted at such positions may be aliphatic, aromatic, or acidic spacer amino acids. Group B melanocortin analogs also comprise Nle at the N-terminus and dVal-dPro at the C-terminus. Group B non-naturally occurring melanocortin analogs are provided in Table 3. Table 3. Non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO B172Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Dap-Trp-Dap]-dVal-dPro-NH2 B273Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dOrn-Trp-Dap]-dVal-dPro-NH2 B374Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dLys-Trp-Dap]-dVal-dPro-NH2 B475Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Orn]-dVal-dPro-NH2 B576Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dab]-dVal-dPro-NH2 B655Ac-Nle-c[Dap-His-dLys-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 B756Ac-Nle-c[Dap-His-p(F)dPhe-Dap-Arg-Trp-Asp]-dVal-dPro-NH2 B857Ac-Nle-c[Dap-His-p(F)dPhe-Lys-Arg-Trp-Asp]-dVal-dPro-NH2 B958Ac-Nle-c[Dap-His-p(F)dPhe-dLys-Arg-Trp-Asp]-dVal-dPro-NH2 B1077Ac-Nle-c[Dap-His-p(F)dPhe-Arg-dLys-Trp-Asp]-dVal-dPro-NH2

[0173] Group C included non-naturally occurring melanocortin analogs C1 to C3, all of which are cyclic peptides comprising derivatives of the motif His-p(F)dPhe-Arg-Trp (SEQ ID NO: 106). Group G melanocortin analogs also comprise an alanine residue insertion, -61- 168588233.2Docket No.: 183B-416029-WO resulting in an expanded cycle, Nle at the N-terminus, and dVal-dPro at the C-terminus. Group C non-naturally occurring melanocortin analogs are provided in Table 4. Table 4. Non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO C189Ac-Nle-c[Asp-Arg-p(F)dPhe-His-Ala-Trp-Dap]-dVal-dPro-NH2 C290Ac-Nle-c[Asp-p(F)dPhe-Arg-Ala-His-Trp-Dap]-dVal-dPro-NH2 C391Ac-Nle-c[Asp-Arg-p(F)dPhe-Ala-His-Trp-Dap]-dVal-dPro-NH2

[0174] Group D included non-naturally occurring melanocortin analogs D1 to D2, which are cyclic peptides comprising derivatives of the motif His-p(F)dPhe-Arg-Trp (SEQ ID NO: 106). Group D melanocortin analogs also comprise Nle at the N-terminus and dVal-dPro at the C-terminus. Group D non-naturally occurring melanocortin analogs are provided in Table 5. Table 5. Non-naturally occurring melanocortin analogs Melanocortin SEQ ID analog NO Formula D192Ac-Nle-c[Glu-p(F)dPhe-His-Arg-Trp-Orn]-dVal-dPro-NH2 D293Ac-Nle-c[Glu-His-Trp-Arg-p(F)dPhe-Orn]-dVal-dPro-NH2

[0175] Group E included non-naturally occurring melanocortin analogs E1 to E12, all of which are cyclic peptides comprising the motif His-dNal(2’)-Arg-Trp, or a derivative thereof. Derivatives of the motif His-dNal(2’)-Arg-Trp may include substitution of dNal(2’) for another aromatic residue, such as dPhe. Group E melanocortin analogs also comprise an expanded cycle and dVal-dPro at the C-terminus. Group E non-naturally occurring melanocortin analogs are provided in Table 6. Table 6. Non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO E194Ac-dOrn-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 E295Ac-dAsp-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 E396Ac-dOrn-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 E497Ac-dAsp-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 E598Ac-dPhg-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 E699Ac-dPhe-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 -62- 168588233.2Docket No.: 183B-416029-WO E7100Ac-dPhe-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 E8101Ac-dAsp-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 E9 Ac-dAsp-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro- 102 NH2 E10103Ac-dPhe-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 E11 Ac-dPhe-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro- 104 NH2 E12105Ac-dAsp-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 Agonist activity of melanocortin analogs on melanocortin 1 receptor and melanocortin 5 receptor

[0176] Administration of all the exemplary non-naturally occurring melanocortin analogs activated melanocortin 1 receptor (MC1R) activity, while several also activated melanocortin 5 receptor (MC5R) activity, typically with lower binding affinity, as measured by cAMP levels (Table 7). Table 7. Dose-response results of melanocortin analogs and control against the melanocortin 1 receptor (MC1R) and the melanocortin 5 receptor (MC5R) MC1R MC5R Compound ID Max Activation Max Activation EC50 (nM) (Emax) EC50 (nM) (Emax) NDP-a-MSH 0.39 101.060.12 101.44A1 ** A * C A2 *** A ** A A3 ** A ** A A4 ** A * A A5 ** A ** A A6 ** A * C A7 *** A *** A A8 *** A ** A A9 ** A * A A10 *** A ** A A11 *** A ** A A12 *** A * A A13 ** A ** A A14 *** A ** A A15 ** A * A A16 ** A * A A17 ** A ** A -63- 168588233.2Docket No.: 183B-416029-WO A18 *** A * A A19 *** A ** A A20 ** A * A A21 *** A ** A A22 ** A * A A23 *** A * A A24 *** A * A A25 *** A * A B1 *** A ** A B2 *** A * A B3 *** A * A B4 *** A ** A B5 *** A * C B6 * A * C B7 *** A * A B8 *** A * A B9 ** A * C B10 *** A * A C1 *** A ** A C2 * A * C C3 ** A * A D1 * A * C D2 *** A ** A E1 ** A ** A E2 ** A * A E3 ** A ** A E4 * A * A E5 ** A ** A E6 ** A ** A E7 ** A ** A E8 ** A * A E9 ** A * A E10 ** A ** A E11 ** A ** A E12 ** A * C *** = < 1 nM ** = 1 nM to 100 nM * = > 100 nM A = > 80% Emax B = 50 - 80% Emax C = < 50% Emax -64- 168588233.2Docket No.: 183B-416029-WO Agonist activity of melanocortin analogs on melanocortin 3 receptor and melanocortin 4 receptor

[0177] Administration of a few of the non-naturally occurring melanocortin analogs activated melanocortin 3 receptor (MC3R) and / or melanocortin 4 receptor (MC4R) activity, albeit with low binding affinity, as measured by cAMP levels (Table 8). Table 8. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and the melanocortin 4 receptor (MC4R) MC3R MC4R Compound ID EC50 (nM) Max Activation EC50 (nM) Max Activation (Emax) (Emax) NDP-a-MSH 0.39 101.060.12 101.44A1 * C * A A2 * C * A A3 * C * A A4 * C * C A5 * C * A A6 * C * A A7 * C * A A8 * C * A A9 * C * A A10 * C * A A11 * C * A A12 * C * A A13 * C * A A14 * C * A A15 * C * C A16 * C * A A17 * C * A A18 * C * C A19 * C * A A20 * C * A A21 * C * C A22 * C * A A23 * C * A A24 * C * A A25 * C * A B1 * C * A -65- 168588233.2Docket No.: 183B-416029-WO B2 * C * A B3 * C * A B4 * C * A B5 * C * A B6 * C * C B7 * C * A B8 * C * C B9 * C * A B10 * C * A C1 * C * C C2 * C * C C3 * C * A D1 * C * C D2 * A * C E1 * C * C E2 * C * C E3 * C * C E4 * C * C E5 * C * C E6 * C * C E7 * C * C E8 * C * C E9 * C * C E10 * C * C E11 * C * C E12 * C * A *** = < 1 nM ** = 1 nM to 100 nM * = > 100 nM A = > 80% Emax B = 50 - 80% Emax C = < 50% Emax -66- 168588233.2Docket No.: 183B-416029-WO Antagonist activity of melanocortin analogs on melanocortin 3 receptor and melanocortin 4 receptor

[0178] Administration of none of the non-naturally occurring melanocortin analogs inhibited melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) activity with any substantial binding affinity, as measured by cAMP levels (Table 9). Table 9. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and the melanocortin 4 receptor (MC4R) MC4R MC4R Compound ID EC50 (nM) Max Activation EC50 (nM) Max Activation (Emax) (Emax) NDP-a-MSH 0.39 101.060.12 101.44A1 * C * C A2 * C * C A3 * C * C A4 * C * C A5 * C * C A6 * C * C A7 * C * C A8 * C * C A9 * C * C A10 * C * C A11 * C * C A12 * C * C A13 * C * C A14 * C * C A15 * C * C A16 * C * C A17 * C * C A18 * C * C A19 * C * C A20 * C * C A21 * C * C A22 * A * C A23 * C * C A24 * C * C A25 * C * C B1 * C * C -67- 168588233.2Docket No.: 183B-416029-WO B2 * C * C B3 * C * C B4 * C * C B5 * C * C B6 * C * C B7 * C * C B8 * C * C B9 * C * C B10 * C * C C1 * C * C C2 * C * C C3 * C * C D1 * C * C D2 * C * C E1 * C * A E2 * C * C E3 * C * A E4 * C * C E5 * C * A E6 * C * C E7 * C * A E8 * C * C E9 * C * C E10 * C * A E11 * C * C E12 * C * C * = > 100 nM A = > 80% Emax B = 50 - 80% Emax C = < 50% Emax Additional Embodiments

[0179] Various embodiments of the present technology are set forth below in paragraphs

[0180] to

[0241] :

[0180] 1. A non-naturally occurring melanocortin analog comprising a sequence of Formula (I): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(I), wherein: -68- 168588233.2Docket No.: 183B-416029-WO X1is selected from the group consisting of norleucine (Nle), D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), tryptophan (Trp), and parafluoro-D-phenylalanine (p(F)dPhe); R4is selected from the group consisting of D-2’-naphthylalanine (dNal(2’)), p(F)dPhe, dPhe, His, Arg, and Trp; R5is selected from the group consisting of Arg, p(F)dPhe, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, Lys, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), dPhg, and p(F)dPhe; R7is absent or Trp; R8is selected from the group consisting of ornithine (Orn), 2,4-diaminobutyric acid (Dab), Asp, Dap, and Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, a lactam bridge between R1and R8, when R1is Asp, R2is absent, R6is Lys or Ala, R7is Trp, R4is p(F)dPhe, and R8is Dab or Orn, a lactam bridge between R1and R8, when R1is Asp, R2and R7are absent, R4is dPhe or dNal(2’), and R8is Lys, and -69- 168588233.2Docket No.: 183B-416029-WO a lactam bridge between R1and R8, when R1is Glu, R2and R7are absent, R4is His or Arg and R8is Orn, provided that: when R4is dPhe, then X1is dAsp and X2-X3are absent, when R4is dNal(2’), then (i) X1is dAsp and X2is not dAla when X3is absent, (ii) X1is dOrn, X2is absent or dAla, and X3is absent (iii) X1is dPhe and X2is Gly or dAla, or (iv) X1is dPhg, X2is dAla, and X3is absent, when R4is p(F)dPhe, then (i) R5is Arg and R3and R6are not Arg, wherein when R6is Ala or dAla, then R8is Dab or Asp, when R6is Lys, then R8is Dab or Orn, and when R6is Dap, then R8is Dap, or (ii) R5is not Arg, wherein when R5is dPhe, then R8is not Dap, and when R4is Arg or His, then R5is not His, and R6is not Arg.

[0181] 2. The non-naturally occurring melanocortin analog of embodiment 1, wherein: X1is selected from the group consisting of norleucine (Nle), D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), tryptophan (Trp), and parafluoro-D-phenylalanine (p(F)dPhe); R4is selected from the group consisting of D-2’-naphthylalanine (dNal(2’)), p(F)dPhe, dPhe, His, Arg, and Trp; R5is selected from the group consisting of Arg, p(F)dPhe, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); -70- 168588233.2Docket No.: 183B-416029-WO R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, Lys, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), dPhg, and p(F)dPhe; R7is absent or Trp; R8is selected from the group consisting of ornithine (Orn), 2,4-diaminobutyric acid (Dab), Asp, Dap, and Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, a lactam bridge between R1and R8, when R1is Asp, R2is absent, R6is Lys or Ala, R7is Trp, R4is p(F)dPhe, and R8is Dab or Orn, a lactam bridge between R1and R8, when R1is Asp, R2and R7are absent, R4is dPhe or dNal(2’), and R8is Lys, and a lactam bridge between R1and R8, when R1is Glu, R2and R7are absent, R4is His or Arg and R8is Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-dPhg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 2); Ac-dOrn-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-dOrn-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4); Ac-dAsp-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 5); Ac-dAsp-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 6); Ac-dPhg-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 7); Ac-dPhg-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); Ac-dPhe-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 9); -71- 168588233.2Docket No.: 183B-416029-WO Ac-dPhe-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 10); Ac-dOrn-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 11); Ac-dOrn-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 12); Ac-dAsp-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 13); Ac-dAsp-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 14); Ac-dPhg-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-dPhg-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-dPhe-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-dPhe-dAla-dAla-c[Asp-His-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: 19); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 20); Ac-Nle-c[Asp-dLys-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 21); Ac-Nle-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 22); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 23) Ac-Nle-c[Asp-His-dPhe-Asp-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 24); Ac-Nle-c[Asp-His-dPhe-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 25); Ac-Nle-c[Asp-His-dPhe-Ala-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 26); Ac-dOrn-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27); Ac-dOrn-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 28); Ac-dPhg-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 29); Ac-dAsp-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 30); Ac-dPhe-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 31); Ac-dPhg-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-dOrn-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 33); -72- 168588233.2Docket No.: 183B-416029-WO Ac-dPhg-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34); Ac-dPhg-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 35); Ac-Nle-c[Asp-Trp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 36); Ac-Nle-c[Asp-His-dNal(2')-Asp-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 37); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 40); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAla-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Dap-Trp-Dab]-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Dap-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Lys-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-His-Arg-p(F)dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[Asp-His-p(F)dPhe-dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 47); Ac-Nle-c[Asp-p(F)dPhe-Arg-His-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Nle-c[Glu-p(F)dPhe-Arg-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 49); and Ac-Nle-c[Asp-p(F)dPhe-His-Ala-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 50), wherein c represents cyclization through a lactam bond between R1and R8.

[0182] 3. The non-naturally occurring melanocortin analog of embodiment 1 or 2, wherein the sequence of Formula (I) is a sequence of Formula (IA): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(IA) (SEQ ID NO: 51), wherein: X1is selected from the group consisting of D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); -73- 168588233.2Docket No.: 183B-416029-WO X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent; R3is His; R4is D-2’-naphthylalanine (dNal(2’)) or dPhe; R5is Arg; R6is Trp; R7is absent; R8is lysine (Lys); Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between Asp at R1and Lys at R8, provided that: when R4is dPhe, then X1is dAsp and X2-X3are absent, when R4is dNal(2’), then (i) X1is dAsp and X2is not dAla when X3is absent, (ii) X1is dOrn, X2is absent or dAla, and X3is absent (iii) X1is dPhe and X2is Gly or dAla, or (iv) X1is dPhg, X2is dAla, and X3is absent.

[0183] 4. The non-naturally occurring melanocortin analog of any one of embodiments 1-3, wherein: X1is selected from the group consisting of D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent; R3is His; -74- 168588233.2Docket No.: 183B-416029-WO R4is D-2’-naphthylalanine (dNal(2’)) or dPhe; R5is Arg; R6is Trp; R7is absent; R8is lysine (Lys); Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between Asp at R1and Lys at R8, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-dPhg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 2); Ac-dOrn-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-dOrn-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4); Ac-dAsp-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 5); Ac-dAsp-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 6); Ac-dPhg-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 7); Ac-dPhg-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); Ac-dPhe-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 9); Ac-dPhe-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 10); Ac-dOrn-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 11); Ac-dOrn-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 12); Ac-dAsp-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 13); Ac-dAsp-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 14); Ac-dPhg-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15); -75- 168588233.2Docket No.: 183B-416029-WO Ac-dPhg-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-dPhe-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-dPhe-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 18); Ac-dOrn-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27); Ac-dOrn-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 28); Ac-dPhg-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 29); Ac-dAsp-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 30); Ac-dPhe-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 31); Ac-dPhg-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-dOrn-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 33); Ac-dPhg-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34); and Ac-dPhg-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 35), wherein c represents cyclization through a lactam bond between R1and R8.

[0184] 5. The non-naturally occurring melanocortin analog of any one of embodiments 1-4, wherein 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(IA(i)) (SEQ ID NO: 52), wherein: X1is selected from the group consisting of D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent; R3is His; R4is D-2’-naphthylalanine (dNal(2’)); -76- 168588233.2Docket No.: 183B-416029-WO R5is Arg; R6is Trp; R7is absent; R8is lysine (Lys); Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between Asp at R1and Lys at R8, provided that: when X1is dAsp, then X2is not dAla when X3is absent, when X1is dOrn, then X2is absent or dAla, and X3is absent when X1is dPhe, then X2is Gly or dAla, and when X1is dPhg, then X2is dAla, and X3is absent.

[0185] 6. The non-naturally occurring melanocortin analog of any one of embodiments 1-5, wherein: X1is selected from the group consisting of D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent; R3is His; R4is D-2’-naphthylalanine (dNal(2’)); R5is Arg; R6is Trp; R7is absent; R8is lysine (Lys); Y1is D-valine (dVal); -77- 168588233.2Docket No.: 183B-416029-WO Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between Asp at R1and Lys at R8, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-dOrn-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27); Ac-dOrn-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 28); Ac-dPhg-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 29); Ac-dAsp-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 30); Ac-dPhe-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 31); Ac-dPhg-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-dOrn-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 33); Ac-dPhg-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34); and Ac-dPhg-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 35), wherein c represents cyclization through a lactam bond between R1and R8.

[0186] 7. The non-naturally occurring melanocortin analog of embodiment 1 or 2, wherein the sequence of Formula (I) is a sequence of Formula (IB): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(IB), wherein: X1is norleucine (Nle); R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), tryptophan (Trp), and parafluoro-D-phenylalanine (p(F)dPhe); -78- 168588233.2Docket No.: 183B-416029-WO R4is selected from the group consisting of D-2’-naphthylalanine (dNal(2’)), p(F)dPhe, dPhe, His, Arg, and Trp; R5is selected from the group consisting of Arg, p(F)dPhe, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, Lys, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), dPhg, and p(F)dPhe; R7is absent or Trp; R8is selected from the group consisting of ornithine (Orn), 2,4-diaminobutyric acid (Dab), Asp, Dap, and Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, a lactam bridge between R1and R8, when R1is Asp, R2is absent, R6is Lys or Ala, R7is Trp, R4is p(F)dPhe, and R8is Dab or Orn, a lactam bridge between R1and R8, when R1is Glu, R2and R7are absent, R4is His or Arg and R8is Orn, provided that: when R4is p(F)dPhe, then (i) R5is Arg and R3and R6are not Arg, wherein when R6is Ala or dAla, then R8is Dab or Asp, when R6is Lys, then R8is Dab or Orn, and when R6is Dap, then R8is Dap, or (ii) R5is not Arg, wherein when R5is dPhe, then R8is not Dap, and when R4is Arg or His, then R5is not His, and R6is not Arg.

[0187] 8. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, and 7, wherein: X1is norleucine (Nle); -79- 168588233.2Docket No.: 183B-416029-WO R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), tryptophan (Trp), and parafluoro-D-phenylalanine (p(F)dPhe); R4is selected from the group consisting of D-2’-naphthylalanine (dNal(2’)), p(F)dPhe, dPhe, His, Arg, and Trp; R5is selected from the group consisting of Arg, p(F)dPhe, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, Lys, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), dPhg, and p(F)dPhe; R7is absent or Trp; R8is selected from the group consisting of ornithine (Orn), 2,4-diaminobutyric acid (Dab), Asp, Dap, and Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, a lactam bridge between R1and R8, when R1is Asp, R2is absent, R6is Lys or Ala, R7is Trp, R4is p(F)dPhe, and R8is Dab or Orn, a lactam bridge between R1and R8, when R1is Glu, R2and R7are absent, R4is His or Arg and R8is Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 39); -80- 168588233.2Docket No.: 183B-416029-WO Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 40); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAla-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Dap-Trp-Dab]-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Dap-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Lys-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-His-Arg-p(F)dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[Asp-His-p(F)dPhe-dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 47); Ac-Nle-c[Asp-p(F)dPhe-Arg-His-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Nle-c[Glu-p(F)dPhe-Arg-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 49); and Ac-Nle-c[Asp-p(F)dPhe-His-Ala-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 50), wherein c represents cyclization through a lactam bond between R1and R8.

[0188] 9. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7, and 8, wherein the sequence of Formula (I) or (IB) is a sequence of Formula (IB(i)): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(IB(i)), wherein: X1is norleucine (Nle); R1is aspartic acid (Asp) or 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), and parafluoro-D-phenylalanine (p(F)dPhe); R4is p(F)dPhe or Arg; R5is selected from the group consisting of Arg, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); -81- 168588233.2Docket No.: 183B-416029-WO R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), and dPhg; R7is absent or Trp; R8is Dap or Asp; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, provided that: when R4is p(F)dPhe, then (i) R5is Arg and R3and R6are not Arg, wherein when R6is Ala or dAla, then R8is Asp and when R6is Dap, then R8is Dap, or (ii) R5is not Arg, wherein when R5is dPhe, then R8is not Dap, and when R4is Arg, then R5is not His.

[0189] 10. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, and 7-9, wherein: X1is norleucine (Nle); R1is aspartic acid (Asp) or 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), and parafluoro-D-phenylalanine (p(F)dPhe); R4is p(F)dPhe or Arg; R5is selected from the group consisting of Arg, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), and dPhg; R7is absent or Trp; -82- 168588233.2Docket No.: 183B-416029-WO R8is Dap or Asp; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAla-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Dap-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Lys-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-His-Arg-p(F)dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[Asp-His-p(F)dPhe-dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 47); and Ac-Nle-c[Asp-p(F)dPhe-Arg-His-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 48), wherein c represents cyclization through a lactam bond between R1and R8.

[0190] 11. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, and 7-10, wherein the sequence of Formula (I), (IB), or (IB(i)) is a sequence of Formula (IB(ii)): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(IB(ii)) (SEQ ID NO: 53), wherein: X1is norleucine (Nle); R1is aspartic acid (Asp); R2is absent; R3is His; -83- 168588233.2Docket No.: 183B-416029-WO R4is para-fluoro-D-phenylalanine (p(F)dPhe); R5is selected from the group consisting of His, arginine (Arg), β-glycine (β-Gly), D- aspartic acid (dAsp), D-alanine (dAla), alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), 2,3-diaminopropionic acid (Dap), lysine (Lys), D-lysine (dLys), leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Ala, dAla, Arg, His, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), and dPhg; R7is Trp; R8is Dap; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R1and Dap at R8, provided that: when R5is Arg, then R6is not Arg, wherein when R6is Ala or dAla, then R8is Asp and when R6is Dap, then R8is Dap, and when R5is dPhe, then R8is not Dap.

[0191] 12. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, and 7-11, wherein: X1is norleucine (Nle); R1is aspartic acid (Asp); R2is absent; R3is His; R4is para-fluoro-D-phenylalanine (p(F)dPhe); R5is selected from the group consisting of His, arginine (Arg), β-glycine (β-Gly), D- aspartic acid (dAsp), D-alanine (dAla), alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), 2,3-diaminopropionic acid (Dap), lysine (Lys), D-lysine (dLys), leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Ala, dAla, Arg, His, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), and dPhg; -84- 168588233.2Docket No.: 183B-416029-WO R7is Trp; R8is Dap; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R1and Dap at R8, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAla-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Dap-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Lys-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); and Ac-Nle-c[Asp-His-p(F)dPhe-dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 47), wherein c represents cyclization through a lactam bond between R1and R8.

[0192] 13. The non-naturally occurring melanocortin analog of any one of embodiments 1-12, wherein the N-terminus of the sequence of any one of Formula (I)-(IB(ii)) is acylated.

[0193] 14. The non-naturally occurring melanocortin analog of any one of embodiments 1-13, wherein the N-terminus of the sequence of any one of Formula (I)-(IB(ii)) is acetylated.

[0194] 15. The non-naturally occurring melanocortin analog of any one of embodiments 1-12, wherein the N-terminus of the sequence of any one of Formula (I)-(IB(ii)) is not modified. -85- 168588233.2Docket No.: 183B-416029-WO

[0195] 16. The non-naturally occurring melanocortin analog of any one of embodiments 1-15, wherein the C-terminus of the sequence of any one of Formula (I)-(IB(ii)) is amidated.

[0196] 17. The non-naturally occurring melanocortin analog of any one of embodiments 1-15, wherein the C-terminus of the sequence of any one of Formula (I)-(IB(ii)) is not modified.

[0197] 18. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, and 13-17, wherein X1is Nle and R4is p(F)dPhe.

[0198] 19 The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, and 7-18, wherein R7is absent.

[0199] 20. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, and 7-19, wherein R2is His and R3is β-Gly or dLys.

[0200] 21. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, and 7-20, wherein the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-Nle-c[Asp-His-bGly-p(F)dPhe-Arg-Trp-Dap]-dVal- dPro-NH2 (SEQ ID NO: 107); or Ac-Nle-c[Dap-His-dLys-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro- NH2 (SEQ ID NO: 55), wherein c represents cyclization between R1and R8via a lactam bond.

[0201] 22. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, and 13-18, wherein R2is absent.

[0202] 23. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7-18, and 22, wherein R5is a spacer amino acid, R6is Arg, and R7is Trp.

[0203] 24. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7-18, 22, and 23, wherein R5is selected from Dap, Lys, and dLys.

[0204] 25. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7-18, and 22-24, wherein the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-Nle-c[Dap-His-p(F)dPhe-Dap-Arg-Trp-Asp]- dVal-dPro-NH2 (SEQ ID NO: 56); Ac-Nle-c[Dap-His-p(F)dPhe-Lys-Arg-Trp-Asp]-dVal-dPro- -86- 168588233.2Docket No.: 183B-416029-WO NH2 (SEQ ID NO: 57); and Ac-Nle-c[Dap-His-p(F)dPhe-dLys-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 58), wherein c represents cyclization between R1and R8via a lactam bond.

[0205] 26. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7-18, 22, and 23, wherein R5is selected from Ala, dAla, β-Gly, Ser, dSer, Phe, dPhe, Leu, dAsp, and dPhg.

[0206] 27. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7-18, 22, 23, and 26, wherein the sequence of any one of Formula (I)- (IB(ii)) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Ala-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 59); Ac-Nle-c[Asp-His-p(F)dPhe-dAla-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 60); Ac-Nle-c[Asp-His-p(F)dPhe-bGly-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 108); Ac-Nle-c[Asp-His-p(F)dPhe-Ser-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Asp-His-p(F)dPhe-dSer-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c[Asp-His-p(F)dPhe-Phe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 64); Ac-Nle-c[Asp-His-p(F)dPhe-Leu-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 65); Ac-Nle-c[Asp-His-p(F)dPhe-dAsp-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 66); and Ac-Nle-c[Asp-His-p(F)dPhe-dPhg-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 67), wherein c represents cyclization between R1and R8via a lactam bond.

[0207] 28. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7-18, 22, 23, and 26, wherein the sequence of any one of Formula (I)- (IB(ii)) is selected from the group consisting of: Ac-Nle-c[Dap-His-p(F)dPhe-Ala-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Dap-His-p(F)dPhe-dAla-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Nle-c[Dap-His-p(F)dPhe-Phe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 70); and Ac-Nle-c[Dap-His-p(F)dPhe-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 71), wherein c represents cyclization between R1and R8via a lactam bond. -87- 168588233.2Docket No.: 183B-416029-WO

[0208] 29. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7-18, and 22, wherein R5is Arg, R6is a spacer amino acid, and R7is Trp.

[0209] 30. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7-18, 22, and 29, wherein R6is selected from Dap, dOrn, Lys, and dLys.

[0210] 31. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7-18, 22, 29, and 30, wherein the sequence of any one of Formula (I)- (IB(ii)) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Dap-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dOrn-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dLys-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 75); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dab]-dVal-dPro-NH2 (SEQ ID NO: 76); and Ac-Nle-c[Dap-His-p(F)dPhe-Arg-dLys-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 77), wherein c represents cyclization between R1and R8via a lactam bond.

[0211] 32. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7-18, 22, and 29, wherein R6is selected from Ala, dAla, Ser, dSer, Leu, dLeu, Asp, dAsp, Phg, and dPhg.

[0212] 33. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7-18, 22, 29, and 32, wherein the sequence of any one of Formula (I)- (IB(ii)) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dab]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ser-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dSer-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Leu-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 81); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dLeu-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Asp-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 83); -88- 168588233.2Docket No.: 183B-416029-WO Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAsp-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Phg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 85); and Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dPhg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 86), wherein c represents cyclization between R1and R8via a lactam bond.

[0213] 34. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7-18, 22, 29, and 32, wherein the sequence of any one of Formula (I)- (IB(ii)) is: Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Ala-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 87); or Ac-Nle-c[Dap-His-p(F)dPhe-Arg-dAla-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 88), wherein c represents cyclization between R1and R8via a lactam bond.

[0214] 35. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7-18, and 22, wherein R5is Ala, R6is His, and R7is Trp.

[0215] 36. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7-18, 22, and 35, wherein the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-Nle-c[Asp-Arg-p(F)dPhe-His-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 89); Ac-Nle-c[Asp-p(F)dPhe-Arg-Ala-His-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 90); Ac-Nle-c[Asp-Arg-p(F)dPhe-Ala-His-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 91), wherein c represents cyclization between R1and R8via a lactam bond.

[0216] 37. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, and 13-17, wherein R2and R7are absent.

[0217] 38. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 13-17, and 37, wherein the sequence of any one of Formula (I)-(IB(ii)) is cyclized between Glu at R1and Orn at R8.

[0218] 39. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 7-17, 37, and 38, wherein the sequence of any one of Formula (I)-(IB(ii)) is: Ac-Nle-c[Glu-p(F)dPhe-His-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 92); or Ac-Nle- c[Glu-His-Trp-Arg-p(F)dPhe-Orn]-dVal-dPro-NH2 (SEQ ID NO: 93), wherein c represents cyclization between R1and R8via a lactam bond -89- 168588233.2Docket No.: 183B-416029-WO

[0219] 40. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 13-17, and 37, wherein the sequence of any one of Formula (I)-(IB(ii)) is cyclized between Asp at R1and Lys at R8.

[0220] 41. The non-naturally occurring melanocortin analog of any one of embodiments 1, 2, 13-17, 37, and 40, wherein X1is selected from the group consisting of dOrn, dAsp, dPhg, and dPhe.

[0221] 42. The non-naturally occurring melanocortin analog of any one of embodiments 1-6, 13-17, 37, 40, and 41, wherein R4is dNal(2’).

[0222] 43. The non-naturally occurring melanocortin analog of any one of embodiments 1-6, 13-17, 37, and 40-42, wherein the sequence of any one of Formula (I)- (IB(ii)) is selected from the group consisting of: Ac-dOrn-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 94); Ac-dAsp-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 95); Ac-dOrn-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 96); Ac-dAsp-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 97); Ac-dPhg-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 98); Ac-dPhe-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 99); Ac-dPhe-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-dAsp-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 101); Ac-dAsp-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102); Ac-dPhe-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 103); and Ac-dPhe-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 104), wherein c represents cyclization between R1and R8via a lactam bond.

[0223] 44. The non-naturally occurring melanocortin analog of any one of embodiments 1-6, 13-17, 37, 40, and 41, wherein R4is dPhe. -90- 168588233.2Docket No.: 183B-416029-WO

[0224] 45. The non-naturally occurring melanocortin analog of any one of embodiments 1-6, 13-17, 37, 40, 41, and 44, wherein the sequence of any one of Formula (I)-(IB(ii)) is: Ac-dAsp-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 105), wherein c represents cyclization between R1and R8via a lactam bond.

[0225] 46. The non-naturally occurring melanocortin analog of any one of embodiments 1-45, wherein the non-naturally occurring melanocortin analog is present in a pharmaceutical composition.

[0226] 47. The non-naturally occurring melanocortin analog of embodiment 46, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable salt.

[0227] 48. The non-naturally occurring melanocortin analog of embodiment 46, wherein the pharmaceutical composition further comprises a pharmaceutical carrier.

[0228] 49. The non-naturally occurring melanocortin analog of embodiment 48, wherein the pharmaceutical carrier comprises water.

[0229] 50. The non-naturally occurring melanocortin analog of embodiment 46, wherein the non-naturally occurring melanocortin analog is present in the composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the composition.

[0230] 51. The non-naturally occurring melanocortin analog of embodiment 46, wherein the non-naturally occurring melanocortin analog is present in the composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the composition.

[0231] 52. The non-naturally occurring melanocortin analog of embodiment 46, wherein the non-naturally occurring melanocortin analog is present in the composition in a concentration of about 50 mg / mL, relative to a total volume of the composition.

[0232] 53. The non-naturally occurring melanocortin analog of any one of embodiments 1-52, wherein the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration. -91- 168588233.2Docket No.: 183B-416029-WO

[0233] 54. The non-naturally occurring melanocortin analog of any one of embodiments 46-53, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to a subject parenterally.

[0234] 55. The non-naturally occurring melanocortin analog of any one of embodiments 46-54, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to a subject subcutaneously.

[0235] 56. The non-naturally occurring melanocortin analog of any one of embodiments 1-55, wherein the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of a subject.

[0236] 57. The non-naturally occurring melanocortin analog of any one of embodiments 1-56, wherein a therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.001 mg / kg to 25 mg / kg per body weight of a subject.

[0237] 58. The non-naturally occurring melanocortin analog of any one of embodiments 1-57, wherein a therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.5 mg / kg to 10 mg / kg per body weight of a subject.

[0238] 59. The non-naturally occurring melanocortin analog of any one of embodiments 1-55, wherein 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 per body weight of a subject.

[0239] 60. The non-naturally occurring melanocortin analog of any one of embodiments 1-59, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg per body weight of a subject.

[0240] 61. The non-naturally occurring melanocortin analog of any one of embodiments 1-60, wherein the non-naturally occurring melanocortin analog is administered to a subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

[0241] 62. The non-naturally occurring melanocortin analog of any one of embodiments 1-60, wherein the non-naturally occurring melanocortin analog is administered -92- 168588233.2Docket No.: 183B-416029-WO to a subject for 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

[0242] 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. -93- 168588233.2

Claims

Docket No.: 183B-416029-WO CLAIMS I / We claim:

1. A non-naturally occurring melanocortin analog comprising a sequence of Formula (I): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(I), wherein: X1is selected from the group consisting of norleucine (Nle), D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), tryptophan (Trp), and parafluoro-D-phenylalanine (p(F)dPhe); R4is selected from the group consisting of D-2’-naphthylalanine (dNal(2’)), p(F)dPhe, dPhe, His, Arg, and Trp; R5is selected from the group consisting of Arg, p(F)dPhe, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, Lys, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), dPhg, and p(F)dPhe; R7is absent or Trp; R8is selected from the group consisting of ornithine (Orn), 2,4-diaminobutyric acid (Dab), Asp, Dap, and Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and -94- 168588233.2Docket No.: 183B-416029-WO the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, a lactam bridge between R1and R8, when R1is Asp, R2is absent, R6is Lys or Ala, R7is Trp, R4is p(F)dPhe, and R8is Dab or Orn, a lactam bridge between R1and R8, when R1is Asp, R2and R7are absent, R4is dPhe or dNal(2’), and R8is Lys, and a lactam bridge between R1and R8, when R1is Glu, R2and R7are absent, R4is His or Arg and R8is Orn, provided that: when R4is dPhe, then X1is dAsp and X2-X3are absent, when R4is dNal(2’), then (i) X1is dAsp and X2is not dAla when X3is absent, (ii) X1is dOrn, X2is absent or dAla, and X3is absent (iii) X1is dPhe and X2is Gly or dAla, or (iv) X1is dPhg, X2is dAla, and X3is absent, when R4is p(F)dPhe, then (i) R5is Arg and R3and R6are not Arg, wherein when R6is Ala or dAla, then R8is Dab or Asp, when R6is Lys, then R8is Dab or Orn, and when R6is Dap, then R8is Dap, or (ii) R5is not Arg, wherein when R5is dPhe, then R8is not Dap, and when R4is Arg or His, then R5is not His, and R6is not Arg.

2. The non-naturally occurring melanocortin analog of claim 1, wherein: X1is selected from the group consisting of norleucine (Nle), D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); -95- 168588233.2Docket No.: 183B-416029-WO R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), tryptophan (Trp), and parafluoro-D-phenylalanine (p(F)dPhe); R4is selected from the group consisting of D-2’-naphthylalanine (dNal(2’)), p(F)dPhe, dPhe, His, Arg, and Trp; R5is selected from the group consisting of Arg, p(F)dPhe, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, Lys, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), dPhg, and p(F)dPhe; R7is absent or Trp; R8is selected from the group consisting of ornithine (Orn), 2,4-diaminobutyric acid (Dab), Asp, Dap, and Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, a lactam bridge between R1and R8, when R1is Asp, R2is absent, R6is Lys or Ala, R7is Trp, R4is p(F)dPhe, and R8is Dab or Orn, a lactam bridge between R1and R8, when R1is Asp, R2and R7are absent, R4is dPhe or dNal(2’), and R8is Lys, and a lactam bridge between R1and R8, when R1is Glu, R2and R7are absent, R4is His or Arg and R8is Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-dPhg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 2); Ac-dOrn-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-dOrn-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4); -96- 168588233.2Docket No.: 183B-416029-WO Ac-dAsp-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 5); Ac-dAsp-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 6); Ac-dPhg-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 7); Ac-dPhg-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); Ac-dPhe-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 9); Ac-dPhe-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 10); Ac-dOrn-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 11); Ac-dOrn-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 12); Ac-dAsp-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 13); Ac-dAsp-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 14); Ac-dPhg-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-dPhg-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-dPhe-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-dPhe-dAla-dAla-c[Asp-His-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: 19); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 20); Ac-Nle-c[Asp-dLys-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 21); Ac-Nle-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 22); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 23) Ac-Nle-c[Asp-His-dPhe-Asp-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 24); Ac-Nle-c[Asp-His-dPhe-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 25); Ac-Nle-c[Asp-His-dPhe-Ala-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 26); Ac-dOrn-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27); Ac-dOrn-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 28); -97- 168588233.2Docket No.: 183B-416029-WO Ac-dPhg-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 29); Ac-dAsp-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 30); Ac-dPhe-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 31); Ac-dPhg-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-dOrn-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 33); Ac-dPhg-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34); Ac-dPhg-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 35); Ac-Nle-c[Asp-Trp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 36); Ac-Nle-c[Asp-His-dNal(2')-Asp-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 37); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 40); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAla-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Dap-Trp-Dab]-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Dap-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Lys-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-His-Arg-p(F)dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[Asp-His-p(F)dPhe-dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 47); Ac-Nle-c[Asp-p(F)dPhe-Arg-His-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Nle-c[Glu-p(F)dPhe-Arg-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 49); and Ac-Nle-c[Asp-p(F)dPhe-His-Ala-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 50), wherein c represents cyclization through a lactam bond between R1and R8. -98- 168588233.2Docket No.: 183B-416029-WO 3. The non-naturally occurring melanocortin analog of claim 1 or 2, wherein the sequence of Formula (I) is a sequence of Formula (IA): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(IA) (SEQ ID NO: 51), wherein: X1is selected from the group consisting of D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent; R3is His; R4is D-2’-naphthylalanine (dNal(2’)) or dPhe; R5is Arg; R6is Trp; R7is absent; R8is lysine (Lys); Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between Asp at R1and Lys at R8, provided that: when R4is dPhe, then X1is dAsp and X2-X3are absent, when R4is dNal(2’), then (i) X1is dAsp and X2is not dAla when X3is absent, (ii) X1is dOrn, X2is absent or dAla, and X3is absent (iii) X1is dPhe and X2is Gly or dAla, or (iv) X1is dPhg, X2is dAla, and X3is absent.

4. The non-naturally occurring melanocortin analog of any one of claims 1-3, wherein: -99- 168588233.2Docket No.: 183B-416029-WO X1is selected from the group consisting of D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent; R3is His; R4is D-2’-naphthylalanine (dNal(2’)) or dPhe; R5is Arg; R6is Trp; R7is absent; R8is lysine (Lys); Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between Asp at R1and Lys at R8, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-dPhg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 2); Ac-dOrn-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-dOrn-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4); Ac-dAsp-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 5); Ac-dAsp-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 6); Ac-dPhg-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 7); Ac-dPhg-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); Ac-dPhe-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 9); -100- 168588233.2Docket No.: 183B-416029-WO Ac-dPhe-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 10); Ac-dOrn-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 11); Ac-dOrn-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 12); Ac-dAsp-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 13); Ac-dAsp-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 14); Ac-dPhg-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-dPhg-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-dPhe-Gly-Gly-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-dPhe-dAla-dAla-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 18); Ac-dOrn-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27); Ac-dOrn-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 28); Ac-dPhg-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 29); Ac-dAsp-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 30); Ac-dPhe-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 31); Ac-dPhg-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-dOrn-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 33); Ac-dPhg-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34); and Ac-dPhg-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 35), wherein c represents cyclization through a lactam bond between R1and R8.

5. The non-naturally occurring melanocortin analog of any one of claims 1-4, wherein 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(IA(i)) (SEQ ID NO: 52), wherein: -101- 168588233.2Docket No.: 183B-416029-WO X1is selected from the group consisting of D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent; R3is His; R4is D-2’-naphthylalanine (dNal(2’)); R5is Arg; R6is Trp; R7is absent; R8is lysine (Lys); Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between Asp at R1and Lys at R8, provided that: when X1is dAsp, then X2is not dAla when X3is absent, when X1is dOrn, then X2is absent or dAla, and X3is absent when X1is dPhe, then X2is Gly or dAla, and when X1is dPhg, then X2is dAla, and X3is absent.

6. The non-naturally occurring melanocortin analog of any one of claims 1-5, wherein: X1is selected from the group consisting of D-aspartic acid (dAsp), D-ornithine (dOrn), D-phenylalanine (dPhe), and D-α-phenylglycine (dPhg); X2is absent, glycine (Gly), or D-alanine (dAla); X3is absent, Gly, or dAla; -102- 168588233.2Docket No.: 183B-416029-WO R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent; R3is His; R4is D-2’-naphthylalanine (dNal(2’)); R5is Arg; R6is Trp; R7is absent; R8is lysine (Lys); Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between Asp at R1and Lys at R8, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-dOrn-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27); Ac-dOrn-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 28); Ac-dPhg-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 29); Ac-dAsp-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 30); Ac-dPhe-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 31); Ac-dPhg-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-dOrn-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 33); Ac-dPhg-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34); and Ac-dPhg-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 35), wherein c represents cyclization through a lactam bond between R1and R8. -103- 168588233.2Docket No.: 183B-416029-WO 7. The non-naturally occurring melanocortin analog of claim 1 or 2, wherein the sequence of Formula (I) is a sequence of Formula (IB): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(IB), wherein: X1is norleucine (Nle); R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), tryptophan (Trp), and parafluoro-D-phenylalanine (p(F)dPhe); R4is selected from the group consisting of D-2’-naphthylalanine (dNal(2’)), p(F)dPhe, dPhe, His, Arg, and Trp; R5is selected from the group consisting of Arg, p(F)dPhe, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, Lys, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), dPhg, and p(F)dPhe; R7is absent or Trp; R8is selected from the group consisting of ornithine (Orn), 2,4-diaminobutyric acid (Dab), Asp, Dap, and Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, a lactam bridge between R1and R8, when R1is Asp, R2is absent, R6is Lys or Ala, R7is Trp, R4is p(F)dPhe, and R8is Dab or Orn, -104- 168588233.2Docket No.: 183B-416029-WO a lactam bridge between R1and R8, when R1is Glu, R2and R7are absent, R4is His or Arg and R8is Orn, provided that: when R4is p(F)dPhe, then (i) R5is Arg and R3and R6are not Arg, wherein when R6is Ala or dAla, then R8is Dab or Asp, when R6is Lys, then R8is Dab or Orn, and when R6is Dap, then R8is Dap, or (ii) R5is not Arg, wherein when R5is dPhe, then R8is not Dap, and when R4is Arg or His, then R5is not His, and R6is not Arg.

8. The non-naturally occurring melanocortin analog of any one of claims 1, 2, and 7, wherein: X1is norleucine (Nle); R1is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), and 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), tryptophan (Trp), and parafluoro-D-phenylalanine (p(F)dPhe); R4is selected from the group consisting of D-2’-naphthylalanine (dNal(2’)), p(F)dPhe, dPhe, His, Arg, and Trp; R5is selected from the group consisting of Arg, p(F)dPhe, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, Lys, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), dPhg, and p(F)dPhe; R7is absent or Trp; R8is selected from the group consisting of ornithine (Orn), 2,4-diaminobutyric acid (Dab), Asp, Dap, and Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and -105- 168588233.2Docket No.: 183B-416029-WO the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, a lactam bridge between R1and R8, when R1is Asp, R2is absent, R6is Lys or Ala, R7is Trp, R4is p(F)dPhe, and R8is Dab or Orn, a lactam bridge between R1and R8, when R1is Glu, R2and R7are absent, R4is His or Arg and R8is Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 40); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAla-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Dap-Trp-Dab]-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Dap-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Lys-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-His-Arg-p(F)dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[Asp-His-p(F)dPhe-dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 47); Ac-Nle-c[Asp-p(F)dPhe-Arg-His-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Nle-c[Glu-p(F)dPhe-Arg-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 49); and Ac-Nle-c[Asp-p(F)dPhe-His-Ala-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 50), wherein c represents cyclization through a lactam bond between R1and R8. -106- 168588233.2Docket No.: 183B-416029-WO 9. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7, and 8, wherein the sequence of Formula (I) or (IB) is a sequence of Formula (IB(i)): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(IB(i)), wherein: X1is norleucine (Nle); R1is aspartic acid (Asp) or 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), and parafluoro-D-phenylalanine (p(F)dPhe); R4is p(F)dPhe or Arg; R5is selected from the group consisting of Arg, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), and dPhg; R7is absent or Trp; R8is Dap or Asp; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, provided that: when R4is p(F)dPhe, then (i) R5is Arg and R3and R6are not Arg, wherein when R6is Ala or dAla, then R8is Asp and when R6is Dap, then R8is Dap, or (ii) R5is not Arg, wherein when R5is dPhe, then R8is not Dap, and when R4is Arg, then R5is not His. -107- 168588233.2Docket No.: 183B-416029-WO 10. The non-naturally occurring melanocortin analog of any one of claims 1, 2, and 7-9, wherein: X1is norleucine (Nle); R1is aspartic acid (Asp) or 2,3-diaminopropionic acid (Dap); R2is absent or histidine (His); R3is selected from the group consisting of His, β-glycine (β-Gly), D-lysine (dLys) arginine (Arg), and parafluoro-D-phenylalanine (p(F)dPhe); R4is p(F)dPhe or Arg; R5is selected from the group consisting of Arg, His, β-Gly, dAsp, dAla, alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), Dap, lysine (Lys), dLys, leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Trp, Ala, dAla, Arg, His, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), and dPhg; R7is absent or Trp; R8is Dap or Asp; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via linkage selected from the group consisting of: a lactam bridge between R1and R8, when R1is Asp or Dap, at least one of R2and R7is present, R4is p(F)dPhe, and R8is Dap or Asp, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAla-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Dap-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 44); -108- 168588233.2Docket No.: 183B-416029-WO Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Lys-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-His-Arg-p(F)dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[Asp-His-p(F)dPhe-dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 47); and Ac-Nle-c[Asp-p(F)dPhe-Arg-His-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 48), wherein c represents cyclization through a lactam bond between R1and R8.

11. The non-naturally occurring melanocortin analog of any one of claims 1, 2, and 7-10, wherein the sequence of Formula (I), (IB), or (IB(i)) is a sequence of Formula (IB(ii)): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2(IB(ii)) (SEQ ID NO: 53), wherein: X1is norleucine (Nle); R1is aspartic acid (Asp); R2is absent; R3is His; R4is para-fluoro-D-phenylalanine (p(F)dPhe); R5is selected from the group consisting of His, arginine (Arg), β-glycine (β-Gly), D- aspartic acid (dAsp), D-alanine (dAla), alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), 2,3-diaminopropionic acid (Dap), lysine (Lys), D-lysine (dLys), leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Ala, dAla, Arg, His, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), and dPhg; R7is Trp; R8is Dap; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R1and Dap at R8, provided that: when R5is Arg, then R6is not Arg, wherein when R6is Ala or dAla, then R8is Asp and when R6is Dap, then R8is Dap, and -109- 168588233.2Docket No.: 183B-416029-WO when R5is dPhe, then R8is not Dap.

12. The non-naturally occurring melanocortin analog of any one of claims 1, 2, and 7-11, wherein: X1is norleucine (Nle); R1is aspartic acid (Asp); R2is absent; R3is His; R4is para-fluoro-D-phenylalanine (p(F)dPhe); R5is selected from the group consisting of His, arginine (Arg), β-glycine (β-Gly), D- aspartic acid (dAsp), D-alanine (dAla), alanine (Ala), serine (Ser), D-serine (dSer), phenylalanine (Phe), D-phenylalanine (dPhe), 2,3-diaminopropionic acid (Dap), lysine (Lys), D-lysine (dLys), leucine (Leu), and D-phenylglycine (dPhg); R6is selected from the group consisting of Ala, dAla, Arg, His, dLys, dOrn, Dap, Ser, dSer, Leu, D-leucine (dLeu), Asp, dAsp, phenylglycine (Phg), and dPhg; R7is Trp; R8is Dap; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R1and Dap at R8, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAla-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Dap-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Lys-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); and -110- 168588233.2Docket No.: 183B-416029-WO Ac-Nle-c[Asp-His-p(F)dPhe-dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 47), wherein c represents cyclization through a lactam bond between R1and R8.

13. The non-naturally occurring melanocortin analog of any one of claims 1-12, wherein the N-terminus of the sequence of any one of Formula (I)-(IB(ii)) is acylated.

14. The non-naturally occurring melanocortin analog of any one of claims 1-13, wherein the N-terminus of the sequence of any one of Formula (I)-(IB(ii)) is acetylated.

15. The non-naturally occurring melanocortin analog of any one of claims 1-12, wherein the N-terminus of the sequence of any one of Formula (I)-(IB(ii)) is not modified.

16. The non-naturally occurring melanocortin analog of any one of claims 1-15, wherein the C-terminus of the sequence of any one of Formula (I)-(IB(ii)) is amidated.

17. The non-naturally occurring melanocortin analog of any one of claims 1-15, wherein the C-terminus of the sequence of any one of Formula (I)-(IB(ii)) is not modified.

18. The non-naturally occurring melanocortin analog of any one of claims 1, 2, and 13-17, wherein X1is Nle and R4is p(F)dPhe. 19 The non-naturally occurring melanocortin analog of any one of claims 1, 2, and 7-18, wherein R7is absent.

20. The non-naturally occurring melanocortin analog of any one of claims 1, 2, and 7-19, wherein R2is His and R3is β-Gly or dLys.

21. The non-naturally occurring melanocortin analog of any one of claims 1, 2, and 7-20, wherein the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: -111- 168588233.2Docket No.: 183B-416029-WO Ac-Nle-c[Asp-His-bGly-p(F)dPhe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 107); or Ac-Nle-c[Dap-His-dLys-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 55), wherein c represents cyclization between R1and R8via a lactam bond.

22. The non-naturally occurring melanocortin analog of any one of claims 1, 2, and 13-18, wherein R2is absent.

23. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7- 18, and 22, wherein R5is a spacer amino acid, R6is Arg, and R7is Trp.

24. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7- 18, 22, and 23, wherein R5is selected from Dap, Lys, and dLys.

25. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7- 18, and 22-24, wherein the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-Nle-c[Dap-His-p(F)dPhe-Dap-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-Nle-c[Dap-His-p(F)dPhe-Lys-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 57); and Ac-Nle-c[Dap-His-p(F)dPhe-dLys-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 58), wherein c represents cyclization between R1and R8via a lactam bond.

26. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7- 18, 22, and 23, wherein R5is selected from Ala, dAla, β-Gly, Ser, dSer, Phe, dPhe, Leu, dAsp, and dPhg.

27. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7- 18, 22, 23, and 26, wherein the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Ala-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 59); Ac-Nle-c[Asp-His-p(F)dPhe-dAla-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 60); -112- 168588233.2Docket No.: 183B-416029-WO Ac-Nle-c[Asp-His-p(F)dPhe-bGly-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 108); Ac-Nle-c[Asp-His-p(F)dPhe-Ser-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Asp-His-p(F)dPhe-dSer-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c[Asp-His-p(F)dPhe-Phe-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 64); Ac-Nle-c[Asp-His-p(F)dPhe-Leu-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 65); Ac-Nle-c[Asp-His-p(F)dPhe-dAsp-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 66); and Ac-Nle-c[Asp-His-p(F)dPhe-dPhg-Arg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 67), wherein c represents cyclization between R1and R8via a lactam bond.

28. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7- 18, 22, 23, and 26, wherein the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-Nle-c[Dap-His-p(F)dPhe-Ala-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Dap-His-p(F)dPhe-dAla-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Nle-c[Dap-His-p(F)dPhe-Phe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 70); and Ac-Nle-c[Dap-His-p(F)dPhe-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 71), wherein c represents cyclization between R1and R8via a lactam bond.

29. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7- 18, and 22, wherein R5is Arg, R6is a spacer amino acid, and R7is Trp.

30. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7- 18, 22, and 29, wherein R6is selected from Dap, dOrn, Lys, and dLys.

31. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7- 18, 22, 29, and 30, wherein the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Dap-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 72); -113- 168588233.2Docket No.: 183B-416029-WO Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dOrn-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dLys-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 75); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Lys-Trp-Dab]-dVal-dPro-NH2 (SEQ ID NO: 76); and Ac-Nle-c[Dap-His-p(F)dPhe-Arg-dLys-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 77), wherein c represents cyclization between R1and R8via a lactam bond.

32. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7- 18, 22, and 29, wherein R6is selected from Ala, dAla, Ser, dSer, Leu, dLeu, Asp, dAsp, Phg, and dPhg.

33. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7- 18, 22, 29, and 32, wherein the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ala-Trp-Dab]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Ser-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dSer-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Leu-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 81); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dLeu-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Asp-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 83); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dAsp-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Phg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 85); and Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dPhg-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 86), wherein c represents cyclization between R1and R8via a lactam bond.

34. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7- 18, 22, 29, and 32, wherein the sequence of any one of Formula (I)-(IB(ii)) is: -114- 168588233.2Docket No.: 183B-416029-WO Ac-Nle-c[Dap-His-p(F)dPhe-Arg-Ala-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 87); or Ac-Nle-c[Dap-His-p(F)dPhe-Arg-dAla-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 88), wherein c represents cyclization between R1and R8via a lactam bond.

35. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7- 18, and 22, wherein R5is Ala, R6is His, and R7is Trp.

36. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7- 18, 22, and 35, wherein the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-Nle-c[Asp-Arg-p(F)dPhe-His-Ala-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 89); Ac-Nle-c[Asp-p(F)dPhe-Arg-Ala-His-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 90); Ac-Nle-c[Asp-Arg-p(F)dPhe-Ala-His-Trp-Dap]-dVal-dPro-NH2 (SEQ ID NO: 91), wherein c represents cyclization between R1and R8via a lactam bond.

37. The non-naturally occurring melanocortin analog of any one of claims 1, 2, and 13-17, wherein R2and R7are absent.

38. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 13- 17, and 37, wherein the sequence of any one of Formula (I)-(IB(ii)) is cyclized between Glu at R1and Orn at R8.

39. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 7- 17, 37, and 38, wherein the sequence of any one of Formula (I)-(IB(ii)) is: Ac-Nle-c[Glu-p(F)dPhe-His-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 92); or Ac-Nle-c[Glu-His-Trp-Arg-p(F)dPhe-Orn]-dVal-dPro-NH2 (SEQ ID NO: 93), wherein c represents cyclization between R1and R8via a lactam bond -115- 168588233.2Docket No.: 183B-416029-WO 40. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 13- 17, and 37, wherein the sequence of any one of Formula (I)-(IB(ii)) is cyclized between Asp at R1and Lys at R8.

41. The non-naturally occurring melanocortin analog of any one of claims 1, 2, 13- 17, 37, and 40, wherein X1is selected from the group consisting of dOrn, dAsp, dPhg, and dPhe.

42. The non-naturally occurring melanocortin analog of any one of claims 1-6, 13- 17, 37, 40, and 41, wherein R4is dNal(2’).

43. The non-naturally occurring melanocortin analog of any one of claims 1-6, 13- 17, 37, and 40-42, wherein the sequence of any one of Formula (I)-(IB(ii)) is selected from the group consisting of: Ac-dOrn-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 94); Ac-dAsp-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 95); Ac-dOrn-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 96); Ac-dAsp-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 97); Ac-dPhg-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 98); Ac-dPhe-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 99); Ac-dPhe-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-dAsp-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 101); Ac-dAsp-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102); Ac-dPhe-Gly-Gly-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 103); and Ac-dPhe-dAla-dAla-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 104), wherein c represents cyclization between R1and R8via a lactam bond. -116- 168588233.2Docket No.: 183B-416029-WO 44. The non-naturally occurring melanocortin analog of any one of claims 1-6, 13- 17, 37, 40, and 41, wherein R4is dPhe.

45. The non-naturally occurring melanocortin analog of any one of claims 1-6, 13- 17, 37, 40, 41, and 44, wherein the sequence of any one of Formula (I)-(IB(ii)) is: Ac-dAsp- c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 105), wherein c represents cyclization between R1and R8via a lactam bond.

46. The non-naturally occurring melanocortin analog of any one of claims 1-45, wherein the non-naturally occurring melanocortin analog is present in a pharmaceutical composition.

47. The non-naturally occurring melanocortin analog of claim 46, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable salt.

48. The non-naturally occurring melanocortin analog of claim 46, wherein the pharmaceutical composition further comprises a pharmaceutical carrier.

49. The non-naturally occurring melanocortin analog of claim 48, wherein the pharmaceutical carrier comprises water.

50. The non-naturally occurring melanocortin analog of claim 46, wherein the non- naturally occurring melanocortin analog is present in the composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the composition.

51. The non-naturally occurring melanocortin analog of claim 46, wherein the non- naturally occurring melanocortin analog is present in the composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the composition. -117- 168588233.2Docket No.: 183B-416029-WO 52. The non-naturally occurring melanocortin analog of claim 46, wherein the non- naturally occurring melanocortin analog is present in the composition in a concentration of about 50 mg / mL, relative to a total volume of the composition.

53. The non-naturally occurring melanocortin analog of any one of claims 1-52, wherein the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

54. The non-naturally occurring melanocortin analog of any one of claims 46-53, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to a subject parenterally.

55. The non-naturally occurring melanocortin analog of any one of claims 46-54, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to a subject subcutaneously.

56. The non-naturally occurring melanocortin analog of any one of claims 1-55, wherein the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of a subject.

57. The non-naturally occurring melanocortin analog of any one of claims 1-56, wherein a therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.001 mg / kg to 25 mg / kg per body weight of a subject.

58. The non-naturally occurring melanocortin analog of any one of claims 1-57, wherein a therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.5 mg / kg to 10 mg / kg per body weight of a subject. -118- 168588233.2Docket No.: 183B-416029-WO 59. The non-naturally occurring melanocortin analog of any one of claims 1-55, wherein 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 per body weight of a subject.

60. The non-naturally occurring melanocortin analog of any one of claims 1-59, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg per body weight of a subject.

61. The non-naturally occurring melanocortin analog of any one of claims 1-60, wherein the non-naturally occurring melanocortin analog is administered to a subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

62. The non-naturally occurring melanocortin analog of any one of claims 1-60, wherein the non-naturally occurring melanocortin analog is administered to a subject for 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days. -119- 168588233.2

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