Non-naturally occurring melanocortin receptor agonist analogs for use in pain management and / or substance use disorders

Abstract

Provided herein are non-naturally occurring melanocortin analogs or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof and compositions comprising the same. The melanocortin analogs are agonists or antagonists of melanocortin 3 and / or 4 receptors with sub-micromolar or low-nanomolar binding activity.

Description

Docket No.: 146316.8033.WO02 NON-NATURALLY OCCURRING MELANOCORTIN RECEPTOR AGONIST ANALOGS FOR USE IN PAIN MANAGEMENT AND / OR SUBSTANCE USE DISORDERS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 650,395 filed May 21, 2024; U.S. Provisional Patent Application No.63 / 654,885, filed May 31, 2024; and U.S. Provisional Patent Application No.63 / 683,628, 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 hereby incorporated by reference in its entirety. The xml copy, created on May 20, 2025, is titled “146316_8033_WO02_SL .xml” and is 389,818 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.

[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. -1- 181632343.4Docket No.: 146316.8033.WO02 SUMMARY

[0006] In some aspects, the present technology relates to non-naturally occurring melanocortin analog comprising a sequence according to Formula (I), R1-R2-R3-R4-R5-R6-R7-Y1-Y2(I), wherein: R1is selected from Nle, Arg, and dArg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3is absent, Pro, or Asn; R4is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, Lys, Orn; Y1is absent, dVal, or dArg; Y2is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2and Orn at R7; a lactam bridge between Glu at R2and Lys at R7; a lactam bridge between Asp at R2, R3at Asn, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7, provided that: when R4is p(Cl)dPhe, then R3is Asn, and R1is Nle or Arg, wherein when R1is Nle, then R2is not Lys, R7is not Glu, and the non-naturally occurring melanocortin analog is not cyclized between Asp at R2and Lys at R7or Glu at R2and Orn at R7and when R1is Arg, then R2is not Dap when Y1and Y2are present and R2is not Lys when R7is Asp; -2- 181632343.4Docket No.: 146316.8033.WO02 when R4is p(F)dPhe, then R3is Pro or absent, wherein when R3is absent, R1is not Arg when R2is Lys; when R4is dPhe and R3is Asn, then R1is Arg, R2is Dab, and Y1is dArg; and when R4is dPhe and R3is Pro, then the non-naturally occurring melanocortin analog is not cyclized through a lactam bond between Lys at R2and Glu at R7. DETAILED DESCRIPTION

[0007] Described herein are 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 3 receptor and / or the melanocortin 4 receptor over the melanocortin 1, melanocortin 2, and melanocortin 5 receptors. Some of the melanocortin analogs bind the melanocortin 3 receptor with greater affinity than the melanocortin 4 receptor, whereas other melanocortin antagonists can bind the melanocortin 4 receptor with greater affinity than the melanocortin 3 receptor. Certain melanocortin antagonists bind the melanocortin 3 receptor with the same or generally similar affinity as the melanocortin 4 receptor.

[0008] Each of the non-naturally occurring 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.

[0009] 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.

[0010] The following description is merely exemplary in nature and is not intended to limit the present technology, its applications, or its uses. It should be understood that throughout the drawings, corresponding reference numerals indicate like or corresponding parts and features. The description of specific examples indicated in various embodiments of the present technology are intended for purposes of illustration -3- 181632343.4Docket No.: 146316.8033.WO02 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.

[0011] Furthermore, the detailed description of various embodiments herein makes reference to the accompanying drawing / FIGS, which show various embodiments by way of illustration. 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 and mechanical 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 description, method, system, or process, may be executed in any order and are not limited to the order presented. Moreover, any of the steps or functions thereof may be outsourced to or performed by one or more third parties. Definitions

[0012] 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.

[0013] 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.

[0014] 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. -4- 181632343.4Docket No.: 146316.8033.WO02

[0015] 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.

[0016] 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, 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.

[0017] “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 -5- 181632343.4Docket No.: 146316.8033.WO02 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. The binding to the melanocortin receptor is activating (agonist). 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 contain the pharmacophore: His-Phe-Arg-Trp (SEQ ID NO: 205) or a modified version thereof, or a structural or functional peptide mimetic thereof.

[0018] 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: 205) 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.

[0019] 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.

[0020] A melanocortin receptor “antagonist” or “melanocortin antagonist” is a naturally occurring substance or manufactured drug substance or composition that -6- 181632343.4Docket No.: 146316.8033.WO02 opposes the melanocortin receptor-associated responses normally induced by a melanocortin receptor agonist agent.

[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 “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 -7- 181632343.4Docket No.: 146316.8033.WO02 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 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; -8- 181632343.4Docket No.: 146316.8033.WO02 “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.

[0030] 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. For example, beta (β)-amino acids, the carbon atom to which the amino group is attached is separated from the carboxylate group by one carbon atom, Cβ.

[0031] 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.

[0032] Gamma (γ)-amino acids are amino acids where the carbon atom to which the amino group attaches is separated from the carboxylate moiety by two carbon atoms.

[0033] 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. -9- 181632343.4Docket No.: 146316.8033.WO02

[0034] Additional abbreviations are used as follows: Orn is ornithine; Dab is 2,4- diaminobutanoic acid; Dap is 2,3-diaminopropionic acid; dNal(2’) is D-2’-naphthylalanine; p(Cl)dPhe is para-chloro-D-phenylalanine; and p(F)dPhe is para-fluoro-D-phenylalanine.

[0035] 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.”

[0036] 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.

[0037] An “amine” includes compounds that contain an amine group (-NH2).

[0038] 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.

[0039] 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.”

[0040] “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 aspects, no more than 25% of the administered peptide causes side effects and / or displays a low half-life. More preferably, in some aspects, 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.

[0041] 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. -10- 181632343.4Docket No.: 146316.8033.WO02 Non-naturally Occurring Melanocortin Analogs

[0042] The non-naturally occurring melanocortin analogs of the present technology may comprise a non-naturally occurring melanocortin analog or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Non-naturally occurring melanocortin analogs of the present technology may be selective for the melanocortin 4 receptor (MC4R) and / or melanocortin 3 receptor (MC3R) over other melanocortin receptors, i.e., the melanocortin 1 receptor (MC1R), the melanocortin 2 receptor (MC2R), and the melanocortin 5 receptor (MC5R). Some of the non-naturally occurring melanocortin analogs may bind only the MC3R or the MC4R. Alternatively, some of the non-naturally occurring melanocortin analogs may bind the MC3R with greater affinity than the MC4R, whereas other melanocortin analogs may bind the MC4R with greater affinity than the MC3R. Certain melanocortin analogs may bind the MC3R with the same or generally similar affinity as the MC4R.

[0043] The non-naturally occurring melanocortin analogs of the present technology may be full agonists or full antagonists for one or more melanocortin receptors. A full agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect (Emax) agonist value of greater than or equal to 85%. Similarly, a full antagonist may comprise a non-naturally occurring melanocortin analog having an Emax antagonist value of greater than or equal to 85%.

[0044] The non-naturally occurring melanocortin analogs of the present technology may be partial agonists or partial antagonists. A partial agonist may comprise a non- naturally occurring melanocortin analog having a maximum effect Emax agonist value of less than 85%. Similarly, a partial antagonist may comprise a non-naturally occurring melanocortin analog having an Emax antagonist value of less than 85%.

[0045] If a non-naturally occurring melanocortin analog’s Emax agonist value is greater than it’s Emax antagonist value, then the non-naturally occurring melanocortin analog may be classified as an agonist (e.g., a full agonist or a partial agonist).

[0046] If a non-naturally occurring melanocortin analog’s Emax antagonist value is greater than it’s Emax agonist value, then the non-naturally occurring melanocortin analog may be classified as an antagonist (e.g., a full antagonist or a partial antagonist). -11- 181632343.4Docket No.: 146316.8033.WO02

[0047] The non-naturally occurring melanocortin analogs of the present technology may be one or more of (i) a full MC4R agonist and a full MC3R antagonist; (ii) a full MC4R agonist and a partial MC3R antagonist; and (iii) a full MC4R agonist having no MC3R activity.

[0048] The non-naturally occurring melanocortin analogs of the present technology may avoid cardiac activation typically seen in conventional melanocortin peptide and small molecule agonists. For example, a subject may maintain a stable heart rate, systolic blood pressure, and / or diastolic blood pressure following administration of a melanocortin analog of the present technology.

[0049] The non-naturally occurring melanocortin analogs in accordance with the present technology may have certain structural features that impart specific properties on the analogs, such as, for example, degradation resistance, enhanced epithelial, gastrointestinal, and / or blood brain barrier transport, and binding affinity for the melanocortin 4 receptor and / or melanocortin 3 receptor. Accordingly, in some embodiments, the non-naturally occurring melanocortin analogs have one or more beta hairpin (β-hairpin) and / or beta turn (β-turn) structures. The presence of amino acids that are structurally rigid, such as, for example, Aia, Aba, Ata, Hyp, dHyp, Pro, dPro, transPro(guan), and cisPro(guan), may lead to formation of β-hairpin and / or β-turn structures in the non-naturally occurring melanocortin analog. Additionally, disulfide bridges (e.g., cyclization via disulfide bond) may induce and / or stabilize beta-turn structures of the non-naturally occurring melanocortin analogs. In general, cyclization may stabilize beta-turns, and D-amino acids may induce and / or stabilize beta-turns. Further, in some embodiments, melanocortin analogs include D-valine-D-proline (dVal- dPro) chain as their C-terminus, which may provide enhanced transport and resistance to degradation.

[0050] The presence of certain structural features may impart the non-naturally occurring melanocortin analogs of the present technology with specific binding properties. For example, inclusion of p(F)dPhe or dPhe at the R4position may result in enhanced binding and activation of the melanocortin 4 receptor. Accordingly, melanocortin analogs having p(F)dPhe or dPhe at R4may be full agonists on MC4R. Further, inclusion of Pro at the R3position may result in partial agonism of the -12- 181632343.4Docket No.: 146316.8033.WO02 melanocortin 3 receptor, whereas inclusion of His at the R3position may result in full agonism of the melanocortin 3 receptor.

[0051] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(I), wherein: R1is selected from Nle, Arg, and dArg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3is absent, Pro, or Asn; R4is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, Lys, Orn; Y1is absent, dVal, or dArg; Y2is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2and Orn at R7; a lactam bridge between Glu at R2and Lys at R7; a lactam bridge between Asp at R2, R3at Asn, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7, provided that: when R4is p(Cl)dPhe, then R3is Asn, and R1is Nle or Arg, wherein when R1is Nle, then R2is not Lys, R7is not Glu, and the non-naturally occurring melanocortin analog is not cyclized between Asp at R2and Lys at R7or Glu at R2and Orn at R7and when R1is Arg, then R2is not Dap when Y1and Y2are present and R2is not Lys when R7is Asp; -13- 181632343.4Docket No.: 146316.8033.WO02 when R4is p(F)dPhe, then R3is Pro or absent and R7is not Orn, wherein when R3is absent, R1is not Arg when R2is Lys; when R4is dPhe and R3is Asn, then R1is Arg, R2is Dab, and Y1is dArg; and when R4is dPhe and R3is Pro, then the non-naturally occurring melanocortin analog is not cyclized through a lactam bond between Lys at R2and Glu at R7.

[0052] In some embodiments of the sequence of Formula (I): R1is selected from Nle, Arg, and dArg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3is absent, Pro, or Asn; R4is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, Lys, Orn; Y1is absent, dVal, or dArg; Y2is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2and Orn at R7; a lactam bridge between Glu at R2and Lys at R7; a lactam bridge between Asp at R2, R3at Asn, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Dap-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 25); Ac-Nle-c[Dab-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 26); Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27); -14- 181632343.4Docket No.: 146316.8033.WO02 Ac-Nle-c[Lys-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 28); Ac-Nle-c[Lys-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 29); Ac-Nle-c[Orn-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 30); Ac-Nle-c[Orn-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 31); Ac-Arg-c[Glu-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 189); Ac-Nle-c[Glu-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 190); Ac-Nle-c[Lys-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 196); Ac-Nle-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Arg-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 156); Ac-Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 149); Ac-Arg-c[Asp-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 172); Ac-Arg-c[Lys-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 197); Ac-Arg-c[Lys-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 195); Ac-Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 21); Ac-Nle-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 14); Ac-Nle-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 23); Ac-Nle-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 24); Ac-Nle-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-Nle-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 18); Ac-Nle-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Glu-Asn-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78); -15- 181632343.4Docket No.: 146316.8033.WO02 Ac-Nle-c[Glu-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Lys-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Nle-c[Lys-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 70); Ac-Nle-c[Orn-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-Nle-c[Orn-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 126); Ac-Arg-c[Asp-Asn-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 132); Ac-Arg-c[Asp-Asn-dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 133); Ac-Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 127); Ac-Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 128); Ac-Arg-c[Glu-Asn-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 134); Ac-Arg-c[Glu-Asn-dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 135); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 129); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 130); Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 131); Ac-Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 106); Ac-Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 112); Ac-Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 113); Ac-Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 114); Ac-Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 115); Ac-Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 109); Ac-Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 110); Ac-Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 111); Ac-Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 155); Ac-Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 148); Ac-Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 150); -16- 181632343.4Docket No.: 146316.8033.WO02 Ac-Arg-c[Glu-Asn-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 173); Ac-Arg-c[Glu-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 174); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 168); Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 170); Ac-Arg-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 108); Ac-Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 152); Ac-Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 154); Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 171); Ac-Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 167); Ac-Arg-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 107); Ac-Arg-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 147); Ac-Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 22); Ac-Nle-c[Asp-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 151); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 169); Ac-Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 153); Ac-Nle-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 13); Ac-Nle-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Lys-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 67); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 119); Ac-Arg-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 146); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 158); Ac-Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 166); Ac-Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dArg-dVal-NH2 (SEQ ID NO: 186); -17- 181632343.4Docket No.: 146316.8033.WO02 Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 354); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 355); Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 356); and Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 357).

[0053] In some embodiments of the sequence of Formla (I), R4is p(Cl)dPhe. In some embodiments, the sequence of Formula (I) is a sequence of Formula (IA): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IA), wherein: R1is Nle or Arg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3is Asn; R4is p(Cl)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, Lys, Orn; Y1is absent or dVal; Y2is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu or Asp at R2and Orn or Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7.

[0054] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IA): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IA), wherein: R1is Nle or Arg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3is Asn; -18- 181632343.4Docket No.: 146316.8033.WO02 R4is p(Cl)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, Lys, Orn; Y1is absent or dVal; Y2is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu or Asp at R2and Orn or Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7, provided that: when R1is Nle, then R2is not Lys, R7is not Glu, and the non-naturally occurring melanocortin analog is not cyclized between Asp at R2and Lys at R7or Glu at R2and Orn at R7; and when R1is Arg, then R2is not Dap when Y1and Y2are present and R2is not Lys when R7is Asp.

[0055] In some embodiments of the sequence of Formula (IA): R1is Nle or Arg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3is Asn; R4is p(Cl)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, Lys, Orn; Y1is absent or dVal; Y2is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu or Asp at R2and Orn or Lys at R7; or -19- 181632343.4Docket No.: 146316.8033.WO02 a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Arg-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 156); Ac-Nle-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 119); and Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 158).

[0056] In some embodiments of the sequence of Formla (I), R4is p(F)dPhe. In some embodiments, the sequence of Formula (I) is a sequence of Formula (IB): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IB), wherein: R1is selected from Nle, Arg, and dArg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, and Glu; R3is absent or Pro; R4is p(F)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, and Lys; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through: -20- 181632343.4Docket No.: 146316.8033.WO02 a lactam bridge between Glu at R2and Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7.

[0057] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IB), wherein: R1is selected from Nle, Arg, and dArg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, and Glu; R3is absent or Pro; R4is p(F)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, and Lys; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu at R2and Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7, provided that when R3is absent, R1is not Arg when R2is Lys.

[0058] In some embodiments of the sequence of Formula (IB): R1is selected from Nle, Arg, and dArg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, and Glu; R3is absent or Pro; R4is p(F)dPhe; R5is Arg; -21- 181632343.4Docket No.: 146316.8033.WO02 R6is Trp; R7is selected from the group consisting of Glu, Asp, and Lys; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu at R2and Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence of: Ac-Arg-c[Lys-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 197).

[0059] In some embodiments of the sequence of Formla (I), R4is dPhe. In some embodiments, the sequence of Formula (I) is a sequence of Formula (IC): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IC), wherein: R1is Nle or Arg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, and Glu; R3is absent, Pro, or Asn; R4is dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, and Lys; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu at R2and Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7. -22- 181632343.4Docket No.: 146316.8033.WO02

[0060] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IC), wherein: R1is Nle or Arg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, and Glu; R3is absent, Pro, or Asn; R4is dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, and Lys; Y1is absent, dVal, or dArg; Y2is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu at R2and Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7, provided that: when R3is Asn, then R1is Arg, R2is Dab, and Y1is dArg; and when R3is Pro, then the non-naturally occurring melanocortin analog is not cyclized through a lactam bond between Lys at R2and Glu at R7.

[0061] In some embodiments of the sequence of Formula (IC): R1is Nle or Arg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, and Glu; R3is absent, Pro, or Asn; R4is dPhe; R5is Arg; -23- 181632343.4Docket No.: 146316.8033.WO02 R6is Trp; R7is selected from the group consisting of Glu, Asp, and Lys; Y1is absent, dVal, or dArg; Y2is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu at R2and Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Lys-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Glu-Asn-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Lys-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Nle-c[Lys-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 70); Ac-Nle-c[Orn-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-Nle-c[Orn-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 126); Ac-Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 127); Ac-Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 128); Ac-Arg-c[Glu-Asn-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 134); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 129); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 130); Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 131); Ac-Arg-c[Glu-Asn-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 173); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 168); -24- 181632343.4Docket No.: 146316.8033.WO02 Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 170); Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 171); Ac-Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 167); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 169); Ac-Nle-c[Lys-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 67); Ac-Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 166); and Ac-Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dArg-dVal-NH2 (SEQ ID NO: 186).

[0062] 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, the presence of Pro provides the β-hairpin and / or β-turn structures of the non-naturally occurring melanocortin analog.

[0063] As will be appreciated by the skilled artisan, non-naturally occurring melanocortin analogs comprising a sequence of Formula (I), have an N-terminus and a C-terminus. The melanocortin analogs of the present technology are written beginning with the N-terminus at the left-most amino acid residue and ending with the C-terminus at the right most residue. Accordingly, the N-terminus of a non-naturally melanocortin analog comprising a sequence of Formula (I) may be at R1. Analogously, the C-terminus of a non-naturally occurring melanocortin analog comprising a sequence of Formula (I) may be at any of R7, Y1, and Y2.

[0064] 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 group ).

[0065] In someof the non-naturally occurring melanocortin analog, if present, is not modified.

[0066] In the sequence of Formula (I), Y1Y2or a fragment thereof may represent a C-terminus of the non-naturally occurring melanocortin analog. In some embodiments, Y1and Y2are absent. In some embodiments, Y1and Y2are present. In some -25- 181632343.4Docket No.: 146316.8033.WO02 embodiments, Y1is dVal and Y2is dPro. In other embodiments, Y1is dArg and Y2is dVal.

[0067] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an amide In the sequence of Formula (I), a non-naturally occurring modified by an amide may be represented by a-

[0068] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified. In the sequence of Formula (I), a non-naturally occurring melanocortin analog with an unmodified C-terminus may be represented by - OH.

[0069] In some embodiments of Formula (I), the non-naturally occurring melanocortin analog disclosed herein is cyclized. For example, the non-naturally occurring melanocortin analog can be cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2and Orn at R7; a lactam bridge between Glu at R2and Lys at R7; a lactam bridge between Asp at R2, R3at Asn, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7.

[0070] In some embodiments, R4is p(F)dPhe. In some embodiments, when R4is p(F)dPhe, then R3is Pro. In further embodiments, R1is Nle, R2is selected from the group consisting of Glu, Dap, Dab, Lys or Orn, R5is Arg, R6is Trp and R7is Lys, Asp, or Glu. In still further embodiments, Y1is dVal and Y2is dPro. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c[Dap-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 1); Ac-Nle-c[Dab-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 2); Ac-Nle-c[Lys-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-Nle-c[Lys-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 4); Ac-Nle-c[Orn-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 5); Ac-Nle-c[Orn-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 6); and Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 19), -26- 181632343.4Docket No.: 146316.8033.WO02 wherein c represents cyclization through R2and R7via a lactam bond.

[0071] In other embodiments, R1is dArg, Y1is dVal, and Y2is dPro. In some embodiments, the sequence of Formula (I) is: Ac-dArg-c[Orn-Pro-p(F)dPhe-Arg-Trp- Glu]-dVal-dPro-NH2 (SEQ ID NO: 203), wherein c represents cyclization through R2and R7via a lactam bond.

[0072] In some embodiments, R4is p(Cl)dPhe. In further embodiments, R3is Asn. In some embodiments, R1is Nle, R2is selected from the group consisting of Asp, Glu, Dab, or Orn, R5is Arg, R6is Trp and R7is Lys, Orn, or Asp. In further embodiments, Y1is dVal and Y2is dPro. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 40); Ac-Nle-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 47), wherein c represents cyclization through R2and R7via a lactam bond.

[0073] Alternatively, in some embodiments, R1is Arg, R2is selected from the group consisting of Asp, Glu, Dap, Dab, Lys or Orn, R5is Arg, R6is Trp and R7is Lys, Orn, Asp, or Glu. In some embodiments, Y1is dVal and Y2is dPro. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Arg-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 157); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 159); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 160); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 161); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 162); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 163); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 164); and Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 165), -27- 181632343.4Docket No.: 146316.8033.WO02 wherein c represents cyclization through R2and R7via a lactam bond.

[0074] In other embodiments, Y1and Y2are absent. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 116); Ac-Arg-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 117); Ac-Arg-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 118); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 120); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 121); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 122); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 123); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 124); and Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 125), wherein c represents cyclization through R2and R7via a lactam bond.

[0075] In some embodiments, R4is dPhe. In further embodiments, R3is Pro. In some embodiments, R1is Nle, R2is selected from the group consisting of Asp, Glu, Dab, or Orn, R5is Arg, R6is Trp and R7is Lys, Orn, or Asp. In further embodiments, Y1is dVal and Y2is dPro. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c[Dap-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Nle-c[Dab-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-Nle-c[Lys-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-Nle-c[Orn-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 59); Ac-Nle-c[Orn-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 60); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73), wherein c represents cyclization through R2and R7via a lactam bond.

[0076] In some embodiments, when R4is dPhe, then R3is Asn. In further embodiments, R1is Arg, Y1is dArg and Y2is dVal. In some embodiments, the sequence -28- 181632343.4Docket No.: 146316.8033.WO02 of Formula (I) is: Ac-Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dArg-dVal-NH2 (SEQ ID NO: 185), wherein c represents cyclization through R2and R7via a lactam bond.

[0077] In some embodiments, R4is dPhe or p(F)dPhe. In further embodiments, R3is absent. In still further embodiments, R1is Nle or Arg, R2is Glu or Lys, and R7is Lys or Glu. In still further embodiments, Y1is dVal and Y2is dPro. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Arg-c[Glu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 187); Ac-Nle-c[Glu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 188); Ac-Arg-c[Glu-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 191); Ac-Nle-c[Glu-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 192); Ac-Arg-c[Lys-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 193); Ac-Nle-c[Lys-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 194); and Ac-Nle-c[Lys-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 198), wherein c represents cyclization through R2and R7via a lactam bond.

[0078] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I). In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of SEQ ID NOs: 1-6, 19, 40, 42, 43, 47, 55-57, 59, 60, 73, 116-118, 120-125, 157, 159-165, 185, 187, 188, 191-194, 198, and 203.

[0079] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA). In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of SEQ ID NOs: 40, 42, 43, 47, 116-118, 120-125, 157, and 159-165.

[0080] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB). In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of SEQ ID NOs: 1-6, 19, 191-192, 198, and 203.

[0081] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC). In some embodiments, the non-naturally -29- 181632343.4Docket No.: 146316.8033.WO02 occurring melanocortin analog comprises a sequence of any one of SEQ ID NOs: 55-57, 59, 60, 73, 185, 187, 188, and 193-194. Non-Naturally Occurring Melanocortin Analog Synthesis

[0082] 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 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.

[0083] 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.

[0084] 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).

[0085] 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. -30- 181632343.4Docket No.: 146316.8033.WO02 Specific protecting for solid phase synthesis methods and solution phase synthesis methods groups are known to those having ordinary skill in the art.

[0086] Alpha amino groups may be protected by a suitable protecting group, including a urethane-type protecting group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p-chlorobenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-biphenyl-isopropoxycarbonyl, 9- fluorenylmethoxycarbonyl (Fmoc) and p-methoxybenzyloxycarbonyl (Moz); aliphatic urethane-type protecting groups, such as t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc is useful for alpha amino protection.

[0087] 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.

[0088] 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.

[0089] 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 -31- 181632343.4Docket No.: 146316.8033.WO02 groups may be removed using methods well known in the art for further derivatization of the peptide.

[0090] Reactive groups in a peptide may be selectively modified, either during solid phase synthesis or after removal from the resin. For example, peptides may be modified to obtain N-terminus modifications, such as acetylation, while on resin, or may be removed from the resin by use of a cleaving reagent and then modified. Methods for N- terminus modification, such as acetylation, and for C-terminus modification, such as amidation, are known in the art. Similarly, methods for modifying side chains of amino acids are well known to those skilled in the art of peptide synthesis. The choice of modifications made to reactive groups present on the peptide will be determined, in part, by the characteristics that are desired in the peptide.

[0091] 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).

[0092] 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. -32- 181632343.4Docket No.: 146316.8033.WO02 Salt Forms of Non-Naturally Occurring Melanocortin Analogs

[0093] 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 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.

[0094] 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 -33- 181632343.4Docket No.: 146316.8033.WO02

[0095] The 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.

[0096] In some embodiments, the non-naturally occurring melanocortin analog is present in a composition.

[0097] 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 about 50 mg / mL, relative to a total volume of the composition.

[0098] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) 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 Formula (I) 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 Formula (I) is present in the composition in a concentration of about 50 mg / mL, relative to a total volume of the composition.

[0099] 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.

[0100] 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, -34- 181632343.4Docket No.: 146316.8033.WO02 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 Formula (I).

[0101] In some embodiments, the non-naturally occurring melanocortin analog crosses blood-brain-barrier (BBB) of the subject.

[0102] 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.

[0103] In some embodiments, the subject has a body mass index (BMI) of 18.5 kg / m2to 25 kg / m2. In some embodiments, the subject has a BMI of less than 20 kg / m2. In some embodiments, the subject has a BMI of less than 18.5 kg / m2.

[0104] In some embodiments, the subject is an underweight subject. Underweight subjects include those having a body weight about 3%, 5% or less, 10% or less, 20% or less, or 30% or less, than the lower end of “normal” BMI (e.g., 18.5 kg / m2).

[0105] In some embodiments, the subject has a body mass index (BMI) of greater than 24.9 kg / m2. In some embodiments, the subject has a BMI of 25 kg / m2to 29.9 kg / m2. In some embodiments, the subject has a BMI of greater than or equal to 30 kg / m2.

[0106] In some embodiments, the subject is an overweight subject. Overweight subjects include those having a body weight about 3% or more, 5% or more, 10% or more, 20% or more, or 30% or less, than the upper end of "normal" BMI (e.g., 24.9 kg / m2).

[0107] The compositions 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 -35- 181632343.4Docket No.: 146316.8033.WO02 stability of the non-naturally occurring melanocortin analog, and to reduce adverse injection site reactions.

[0108] The carriers and / or excipients of the 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.

[0109] In some embodiments, the carrier and / or excipient is isotonic.

[0110] 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.

[0111] The carriers and / or excipients of the composition also includes a pH buffered aqueous solution which comprises (a) sodium acetate, (b) Tris, and (c) water.

[0112] 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.

[0113] In some embodiments, the composition includes water in an amount of about 1 wt% to about 90 wt%, about 10 wt% to about 75 wt%, or about 25 wt% to about 50 wt%, relative to a total weight of the composition.

[0114] In some embodiments, sodium acetate 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, 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. -36- 181632343.4Docket No.: 146316.8033.WO02

[0115] In some embodiments, sodium acetate 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, 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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 -37- 181632343.4Docket No.: 146316.8033.WO02 100 mM, 50 mM to 80 mM, or 60 mM to 70 mM, relative to a total volume of the composition.

[0121] In some 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.

[0122] 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.

[0123] In addition to sodium acetate and Tris, the composition can 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] The composition can also comprise a preservative agent. Exemplary preservative agents include, but are not limited to, ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated -38- 181632343.4Docket No.: 146316.8033.WO02 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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, 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. -39- 181632343.4Docket No.: 146316.8033.WO02

[0133] 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.

[0134] The composition disclosed herein in any of its embodiments can be formulated for parenteral administration, such as, for example, in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. The term “parenteral”, as used herein, includes subcutaneous, intravenous, intraperitoneal, intramuscular, and intralesional, or infusion techniques.

[0135] The active ingredient(s) (e.g., the non-naturally occurring melanocortin analog) can 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.

[0136] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises a non-naturally occurring melanocortin analog at a concentration at about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol, or even more, depending on the specific peptide selected, the desired therapeutic response, the route of administration, the formulation and other factors known to those of skill in the art.

[0137] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises sodium acetate at a concentration at about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 76 mM, 77 mM, 78 mM, 79 mM, 80 mM, 81 mM, 82 mM, 83 mM, 84 mM, 85 mM, 86 mM, 87 mM, 88 mM, 89 mM, 90 mM, 91 mM, 92 mM, 93 mM, 94 mM, 95 mM, 96 mM, 97 mM, 98 mM, 99 mM, 100 mM, 105 -40- 181632343.4Docket No.: 146316.8033.WO02 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM.

[0138] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises Tris at a concentration at about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, or 120 mM.

[0139] In some embodiments, the composition comprises one or more antioxidants. For example, the composition may comprise ascorbic acid, cysteine, sodium metabisulfite, propyl gallate, butylated hydroxytoluene, and / or butylated hydroxyanisole.

[0140] In some embodiments, the composition comprises a surfactant, such as a sorbitan ester.

[0141] In some embodiments, the composition comprises a flavoring or scent, such as an aromatic oil. Use of non-naturally occurring melanocortin analogs

[0142] 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 MC3R and / or MC4R. 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 associated with agonizing MC3R and / or MC4R 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 -41- 181632343.4Docket No.: 146316.8033.WO02

[0143] 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.

[0144] 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.

[0145] 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 the subject. In some embodiments, the amount administered is a therapeutically effective amount.

[0146] 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 -42- 181632343.4Docket No.: 146316.8033.WO02 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.

[0147] 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.

[0148] 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

[0149] The following examples are intended to illustrate various embodiments of the present technology. As such, the specific embodiments discussed are not to be construed as limitations on the scope of the present technology. It will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of present technology, and it is understood that such equivalent embodiments, are to be included herein. Further, all references cited herein are hereby incorporated by reference in their entirety, as if fully set forth herein. Example 1: Peptide Synthesis-Generic

[0150] 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.

[0151] 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 -43- 181632343.4Docket No.: 146316.8033.WO02 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.

[0152] 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.

[0153] Initially, the C-terminal amino acid residue of the non-naturally occurring melanocortin analog was coupled to a solid-phase support, e.g., a solid-phase resin. Coupling of the C-terminal amino acid residue and the solid-phase support may be carried out according to any method know in the art. Depending on the coupling method, the alpha-amine of the C-terminal amino acid residue may or may not be protected with an amine protecting group, as described below. Likewise, the carboxyl group of the amino acid residue may or may not be activated prior to coupling to the solid-phase support in order to increase its electrophilicity. Some methods of coupling rely on 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.

[0154] 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, -44- 181632343.4Docket No.: 146316.8033.WO02 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

[0155] 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.

[0156] Additionally, protection of the alpha amino group of an amino acid residue or fragment was performed while that entity reacting with the carboxyl group, followed by the selective removal of the alpha amino protecting group to allow a subsequent reaction to take place at that site. Specific protecting groups for solid phase synthesis methods and solution phase synthesis methods are known to those having ordinary skill in the art. Alpha amino groups were protected by a suitable protecting group, including a urethane- type protecting group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, p-biphenyl-isopropoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc) and p-methoxybenzyloxycarbonyl (Moz); aliphatic urethane-type protecting groups, such as t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc was also used for alpha amino protection. Guanidino groups, if present, were protected by a suitable protecting group, such as nitro, p-toluenesulfonyl (Tos), Z, pentamethylchromanesulfonyl (Pmc), adamantyloxycarbonyl, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and Boc. Pmc was used as a protecting group for Arg.

[0157] 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 -45- 181632343.4Docket No.: 146316.8033.WO02

[0158] 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.

[0159] 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- 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

[0160] 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

[0161] 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, -46- 181632343.4Docket No.: 146316.8033.WO02 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 9 9 Compound

[0162] Compounds were tested for (i) agonist and / or antagonist activity at the human MC3 (FAST-0232C) and MC4 (FAST-0233C) receptors, (ii) agonist activity at the human MC1 (FAST-0230C) receptor, and / or (iii) agonist activity at the human MC5 (FAST-0233C) receptor at the following nanomolar concentrations, in duplicate: 0.0001, 0.001, 0.01, 0.03, 0.1, 0.3, 1, 10, 100, and 1,000. Testing Protocol

[0163] Cyclic AMP (cAMP) Homogenous Time-Resolved Fluorescence (HTRF) assay for Gs coupled receptor:

[0164] 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).

[0165] Dose response curves were performed in parallel with the reference compounds.

[0166] 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. -47- 181632343.4Docket No.: 146316.8033.WO02

[0167] For antagonist test (384well): 5 μl of cells were mixed in the wells of an assay plate with 5 μl of a mix of test compound at increasing concentrations and reference agonist for a final concentration corresponding to the historical EC80. The plates were then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated 1-hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit. Quality Control for Compound Testing

[0168] 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.

[0169] Reference values thus obtained for the test were compared to historical values obtained from the same receptor and used to validate the experimental session.

[0170] 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.

[0171] 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

[0172] Group A included non-naturally occurring melanocortin analogs A1 to A6, all of which are cyclic peptides comprising the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) and cyclized through a lactam bond other than a lactam bond between Asp at R2and Lys at R7. Group A non-naturally occurring melanocortin analogs are provided in Table 2. Table 2. Group A non-naturally occurring melanocortin analogs Melanocortin SEQ ID Sequence-48- 181632343.4Docket No.: 146316.8033.WO02 A6 73Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2llof which are cyclic peptides comprising the motif Pro-p(F)dPhe-Arg-Trp (SEQ ID NO: 358) and cyclized through a lactam bond other than a lactam bond between Asp at R2and Lys at R7. Group B non-naturally occurring melanocortin analogs are provided in Table 3. Table 3. Group P non-naturally occurring melanocortin analogs Melanocortin SEQ ID analog NO Sequence3, all of which are cyclic peptides comprising the motif Asn-p(Cl)dPhe-Arg-Trp (SEQ ID NO: 359) or a derivative thereof and cyclized through a lactam bond. Derivatives of the motif having SEQ ID NO: 359 may include substitution of p(Cl)dPhe for a different aromatic residue, such as, e.g., dPhe. Further, Group C melanocortin analogs have a linear C- terminus of dVal-dPro or dArg-dVal. Group C non-naturally occurring melanocortin analogs are provided in Table 4. Table 4. Group C non-naturally occurring melanocortin analogs Melanocortin SEQ ID Sequence-49- 181632343.4Docket No.: 146316.8033.WO02 C5 157Ac-Arg-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2C6 159Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2ll of which are cyclic peptides comprising the motif Asn-p(Cl)dPhe-Arg-Trp (SEQ ID NO: 359) and cyclized through a lactam bond. Further, Group D melanocortin analogs do not have a linear C-terminus. Group D non-naturally occurring melanocortin analogs are provided in Table 5. Table 5. Group D non-naturally occurring melanocortin analogs Melanocortin SEQ ID analo NO Sequencep y g g , all of which are cyclic peptides comprising the motif dPhe-Arg-Trp or a derivative thereof and cyclized through a lactam bond. Derivatives of the motif dPhe-Arg-Trp may include substitution of dPhe with a different aromatic residue, such as, e.g., p(F)dPhe. Further, -50- 181632343.4Docket No.: 146316.8033.WO02 in Group E melanocortin analogs, R3is absent. Group E non-naturally occurring melanocortin analogs are provided in Table 6. Table 6. Group E non-naturally occurring melanocortin analogs Melanocortin SEQ ID analog NO Sequence5 receptor

[0001] Administration of some non-naturally occurring melanocortin analogs activated melanocortin 1 receptor (MC1R) and melanocortin 5 receptor (MC5R) activity, 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 MC1R MC5R n-51- 181632343.4Docket No.: 146316.8033.WO02 40 C3 0.12 103.10 0.05 104.36 42 C1 0.01 101.99 0.01 102.60-52- 181632343.4Docket No.: 146316.8033.WO02 193 E5 55.80 108.37 73.21 104.94 194 E6 37.48 110.49 153.89 100.00Agonist activity of melanocortin analogs on melanocortin 3 receptor and melanocortin 4 receptor

[0002] Administration of all the non-naturally occurring melanocortin analogs activated melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) activity, as measured by cAMP levels (Table 8). Table 8. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) in agonist mode MC3R MC4R n-53- 181632343.4Docket No.: 146316.8033.WO02 57 A3 *** C *** A 59 A4 *** C *** A*** = < 1 nM -54- 181632343.4Docket No.: 146316.8033.WO02 ** = 1 nM to 100 nM * = > 100 nM A = > 85% Emax B = 50 - 85% Emax C = < 50% Emax Antagonist activity of melanocortin analogs on melanocortin 3 receptor and melanocortin 4 receptor

[0003] Administration of none of the non-naturally occurring melanocortin analogs substantially inhibited melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) activity, as measured by cAMP levels (Table 9). Table 9. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) in antagonist mode MC3R MC4R n-55- 181632343.4Docket No.: 146316.8033.WO02 59 A4 ** B — n.c. — - 60 A5 ** B — n.c. — -*** = < 1 nM ** = 1 nM to 100 nM * = > 100 nM -56- 181632343.4Docket No.: 146316.8033.WO02 A = > 85% Emax B = 50 - 85% Emax C = < 50% Emax Additional Embodiments

[0177] Various embodiments of the present technology are set forth below in paragraphs

[0178] to

[0227] :

[0178] Embodiment 1. A non-naturally occurring melanocortin analog comprising a sequence according to Formula (I), R1-R2-R3-R4-R5-R6-R7-Y1-Y2(I), wherein: R1is selected from Nle, Arg, and dArg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3is absent, Pro, or Asn; R4is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, Lys, Orn; Y1is absent, dVal, or dArg; Y2is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2and Orn at R7; a lactam bridge between Glu at R2and Lys at R7; a lactam bridge between Asp at R2, R3at Asn, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7, provided that: -57- 181632343.4Docket No.: 146316.8033.WO02 when R4is p(Cl)dPhe, then R3is Asn, and R1is Nle or Arg, wherein when R1is Nle, then R2is not Lys, R7is not Glu, and the non-naturally occurring melanocortin analog is not cyclized between Asp at R2and Lys at R7or Glu at R2and Orn at R7and when R1is Arg, then R2is not Dap when Y1and Y2are present and R2is not Lys when R7is Asp; when R4is p(F)dPhe, then R3is Pro or absent, wherein when R3is absent, R1is not Arg when R2is Lys; when R4is dPhe and R3is Asn, then R1is Arg, R2is Dab, and Y1is dArg; and when R4is dPhe and R3is Pro, then the non-naturally occurring melanocortin analog is not cyclized through a lactam bond between Lys at R2and Glu at R7.

[0179] Embodiment 2. The non-naturally occurring melanocortin analog of embodiment 1, wherein: R1is selected from Nle, Arg, and dArg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3is absent, Pro, or Asn; R4is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, Lys, Orn; Y1is absent, dVal, or dArg; Y2is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2and Orn at R7; a lactam bridge between Glu at R2and Lys at R7; a lactam bridge between Asp at R2, R3at Asn, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7, -58- 181632343.4Docket No.: 146316.8033.WO02 provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Dap-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 25); Ac-Nle-c[Dab-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 26); Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27); Ac-Nle-c[Lys-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 28); Ac-Nle-c[Lys-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 29); Ac-Nle-c[Orn-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 30); Ac-Nle-c[Orn-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 31); Ac-Arg-c[Glu-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 189); Ac-Nle-c[Glu-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 190); Ac-Nle-c[Lys-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 196); Ac-Nle-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Arg-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 156); Ac-Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 149); Ac-Arg-c[Asp-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 172); Ac-Arg-c[Lys-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 197); Ac-Arg-c[Lys-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 195); Ac-Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 21); Ac-Nle-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 14); Ac-Nle-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 23); Ac-Nle-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 24); Ac-Nle-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 15); -59- 181632343.4Docket No.: 146316.8033.WO02 Ac-Nle-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 18); Ac-Nle-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Glu-Asn-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Glu-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Lys-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Nle-c[Lys-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 70); Ac-Nle-c[Orn-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-Nle-c[Orn-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 126); Ac-Arg-c[Asp-Asn-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 132); Ac-Arg-c[Asp-Asn-dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 133); Ac-Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 127); Ac-Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 128); Ac-Arg-c[Glu-Asn-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 134); Ac-Arg-c[Glu-Asn-dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 135); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 129); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 130); Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 131); Ac-Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 106); Ac-Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 112); Ac-Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 113); Ac-Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 114); Ac-Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 115); Ac-Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 109); -60- 181632343.4Docket No.: 146316.8033.WO02 Ac-Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 110); Ac-Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 111); Ac-Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 155); Ac-Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 148); Ac-Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 150); Ac-Arg-c[Glu-Asn-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 173); Ac-Arg-c[Glu-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 174); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 168); Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 170); Ac-Arg-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 108); Ac-Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 152); Ac-Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 154); Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 171); Ac-Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 167); Ac-Arg-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 107); Ac-Arg-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 147); Ac-Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 22); Ac-Nle-c[Asp-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 151); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 169); Ac-Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 153); Ac-Nle-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 13); Ac-Nle-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Lys-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 67); -61- 181632343.4Docket No.: 146316.8033.WO02 Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 119); Ac-Arg-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 146); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 158); Ac-Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 166); Ac-Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dArg-dVal-NH2 (SEQ ID NO: 186); Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 354); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 355); Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 356); and Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ D NO: 357).

[0180] Embodiment 3. The non-naturally occurring melanocortin analog of embodiment 1 or 2, wherein the sequence of Formula (I) is a sequence of Formula (IA): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IA), wherein: R1is Nle or Arg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3is Asn; R4is p(Cl)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, Lys, Orn; Y1is absent or dVal; Y2is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu or Asp at R2and Orn or Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7.

[0181] Embodiment 4. The non-naturally occurring melanocortin analog of embodiment 1 or 2, wherein the sequence of Formula (I) is a sequence of Formula (IB): -62- 181632343.4Docket No.: 146316.8033.WO02 R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IB), wherein: R1is selected from Nle, Arg, and dArg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, and Glu; R3is absent or Pro; R4is p(F)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, and Lys; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu at R2and Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7.

[0182] Embodiment 5. The non-naturally occurring melanocortin analog of embodiment 1 or 2, wherein the sequence of Formula (I) is a sequence of Formula (IC): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IC), wherein: R1is Nle or Arg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, and Glu; R3is absent, Pro, or Asn; R4is dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, and Lys; Y1is dVal; -63- 181632343.4Docket No.: 146316.8033.WO02 Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu at R2and Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7.

[0183] Embodiment 6. The non-naturally occurring melanocortin analog of any one of embodiments 1-5, wherein the N-terminus is modified by an acyl group.

[0184] Embodiment 7. The non-naturally occurring melanocortin analog of embodiment 6, wherein the acyl group is acetyl group.

[0185] Embodiment 8. The non-naturally occurring melanocortin analog of any one of embodiments 1-7, wherein the N-terminus is modified by an amide group.

[0186] Embodiment 9. The non-naturally occurring melanocortin analog of any one of embodiments 1-8, wherein R4is p(F)dPhe.

[0187] Embodiment 10. The non-naturally occurring melanocortin analog of any one of embodiments 1-9, wherein R3is Pro.

[0188] Embodiment 11. The non-naturally occurring melanocortin analog of any one of embodiments 1-10, wherein R1is Nle.

[0189] Embodiment 12. The non-naturally occurring melanocortin analog of embodiment 11, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c[Dap-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 1); Ac-Nle-c[Dab-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 2); Ac-Nle-c[Lys-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-Nle-c[Lys-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 4); Ac-Nle-c[Orn-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 5); Ac-Nle-c[Orn-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 6); and Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 19), wherein c represents cyclization through R2and R7via a lactam bond. -64- 181632343.4Docket No.: 146316.8033.WO02

[0190] Embodiment 13. The non-naturally occurring melanocortin analog of any one of embodiments 1-10, wherein R1is dArg.

[0191] Embodiment 14. The non-naturally occurring melanocortin analog of embodiment 13, wherein the sequence of Formula (I) is: Ac-dArg-c[Orn-Pro-p(F)dPhe- Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 203), wherein c represents cyclization through R2and R7via a lactam bond.

[0192] Embodiment 15. The non-naturally occurring melanocortin analog of any one of embodiments 1-8, wherein R4is p(Cl)dPhe.

[0193] Embodiment 16. The non-naturally occurring melanocortin analog of any one of embodiments 1-8 and 15, wherein R3is Asn.

[0194] Embodiment 17. The non-naturally occurring melanocortin analog of any one of embodiments 1-8, 15, and 16, wherein R1is Nle.

[0195] Embodiment 18. The non-naturally occurring melanocortin analog of embodiment 17, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 40); Ac-Nle-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 47), wherein c represents cyclization through R2and R7via a lactam bond.

[0196] Embodiment 19. The non-naturally occurring melanocortin analog of any one of embodiments 1-8, 15, and 16, wherein R1is Arg.

[0197] Embodiment 20. The non-naturally occurring melanocortin analog of any one of embodiments 1-8, 15, 16, and 19, wherein Y1is dVal and Y2is dPro.

[0198] Embodiment 21. The non-naturally occurring melanocortin analog of embodiment 20, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Arg-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 157); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 159); -65- 181632343.4Docket No.: 146316.8033.WO02 Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 160); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 161); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 162); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 163); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 164); and Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 165), wherein c represents cyclization through R2and R7via a lactam bond.

[0199] Embodiment 22. The non-naturally occurring melanocortin analog of any one of embodiments 1-8, 15, 16, and 19, wherein Y1and Y2are absent.

[0200] Embodiment 23. The non-naturally occurring melanocortin analog of embodiment 22, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 116); Ac-Arg-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 117); Ac-Arg-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 118); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 120); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 121); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 122); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 123); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 124); and Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 125), wherein c represents cyclization through R2and R7via a lactam bond.

[0201] Embodiment 24. The non-naturally occurring melanocortin analog of any one of embodiments 1-8, wherein R4is dPhe.

[0202] Embodiment 25. The non-naturally occurring melanocortin analog of any one of embodiments 1-8 and 24, wherein R3is Pro. -66- 181632343.4Docket No.: 146316.8033.WO02

[0203] Embodiment 26. The non-naturally occurring melanocortin analog of any one of embodiments 1-8, 24, and 25, wherein R1is Nle.

[0204] Embodiment 27. The non-naturally occurring melanocortin analog of embodiment 26, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c[Dap-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Nle-c[Dab-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-Nle-c[Lys-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-Nle-c[Orn-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 59); Ac-Nle-c[Orn-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 60); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73), wherein c represents cyclization through R2and R7via a lactam bond.

[0205] Embodiment 28. The non-naturally occurring melanocortin analog of any one of embodiments 1-8 and 30, wherein R3is Asn.

[0206] Embodiment 29. The non-naturally occurring melanocortin analog of embodiment 28, wherein the sequence of Formula (I) is: Ac-Arg-c[Dab-Asn-dPhe-Arg- Trp-Asp]-dArg-dVal-NH2 (SEQ ID NO: 185), wherein c represents cyclization through R2and R7via a lactam bond.

[0207] Embodiment 30. The non-naturally occurring melanocortin analog of any one of embodiments 1-8, wherein R4is dPhe or p(F)dPhe.

[0208] Embodiment 31. The non-naturally occurring melanocortin analog of any one of embodiments 1-8 and 30, wherein R3is absent.

[0209] Embodiment 32. The non-naturally occurring melanocortin analog of embodiment 31, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Arg-c[Glu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 187); Ac-Nle-c[Glu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 188); Ac-Arg-c[Glu-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 191); -67- 181632343.4Docket No.: 146316.8033.WO02 Ac-Nle-c[Glu-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 192); Ac-Arg-c[Lys-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 193); Ac-Nle-c[Lys-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 194); and Ac-Nle-c[Lys-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 198), wherein c represents cyclization through R2and R7via a lactam bond.

[0210] Embodiment 33. The non-naturally occurring melanocortin analog of any one of embodiments 1-32, wherein the sequence of Formula (I) is selected from the group consisting of SEQ ID NOs: 1-6, 19, 40, 42, 43, 47, 55-57, 59, 60, 73, 116-118, 120-125, 157, 159-165, 185, 187, 188, 191-194, 198, and 203.

[0211] 34. The non-naturally occurring melanocortin analog of any one of embodiments 1-33, wherein the non-naturally occurring melanocortin analog is present in a composition.

[0212] Embodiment 35. The non-naturally occurring melanocortin analog of embodiment 34, wherein the composition further comprises a pharmaceutical salt.

[0213] Embodiment 36. The non-naturally occurring melanocortin analog of embodiment 34, wherein the composition further comprises a pharmaceutical carrier.

[0214] Embodiment 37. The non-naturally occurring melanocortin analog of embodiment 34, wherein the pharmaceutical carrier comprises water

[0215] Embodiment 38. The non-naturally occurring melanocortin analog of embodiment 34, 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.

[0216] Embodiment 39. The non-naturally occurring melanocortin analog of embodiment 38, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (I)and 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.

[0217] Embodiment 40. The non-naturally occurring melanocortin analog of embodiment 39, wherein the non-naturally occurring melanocortin analog is present in -68- 181632343.4Docket No.: 146316.8033.WO02 the composition in a concentration of about 50 mg / mL, relative to a total volume of the composition.

[0218] Embodiment 41. The non-naturally occurring melanocortin analog of any one of embodiments 1-40, wherein the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

[0219] Embodiment 42. The non-naturally occurring melanocortin analog of any one of embodiments 34-41, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally.

[0220] Embodiment 43. The non-naturally occurring melanocortin analog of any one of embodiments 34-42, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.

[0221] Embodiment 44. The non-naturally occurring melanocortin analog of any one of embodiments 1-43, wherein the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of the subject.

[0222] Embodiment 45. The non-naturally occurring melanocortin analog of any one of embodiments 1-44, wherein the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

[0223] Embodiment 46. The non-naturally occurring melanocortin analog of any one of embodiments 1-45, wherein the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.5 mg / kg to 10 mg / kg per body weight of the subject.

[0224] Embodiment 47. The non-naturally occurring melanocortin analog of any one of embodiments 1-46, 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 the subject.

[0225] Embodiment 48. The non-naturally occurring melanocortin analog of any one of embodiments 1-47, 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 the subject. -69- 181632343.4Docket No.: 146316.8033.WO02

[0226] Embodiment 49. The non-naturally occurring melanocortin analog of any one of embodiments 1-48, wherein the non-naturally occurring melanocortin analog is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

[0227] Embodiment 50. The non-naturally occurring melanocortin analog of any one of embodiments 1-49, wherein the non-naturally occurring melanocortin analog is administered to the 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.

[0228] 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. -70- 181632343.4

Claims

Docket No.: 146316.8033.WO02 CLAIMS I / We claim:

1. A non-naturally occurring melanocortin analog comprising a sequence according to Formula (I), R1-R2-R3-R4-R5-R6-R7-Y1-Y2(I), wherein: R1is selected from Nle, Arg, and dArg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3is absent, Pro, or Asn; R4is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, Lys, Orn; Y1is absent, dVal, or dArg; Y2is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2and Orn at R7; a lactam bridge between Glu at R2and Lys at R7; a lactam bridge between Asp at R2, R3at Asn, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7, provided that: when R4is p(Cl)dPhe, then R3is Asn, and R1is Nle or Arg, wherein when R1is Nle, then R2is not Lys, R7is not Glu, and the non-naturally occurring melanocortin analog is not cyclized between Asp at R2and Lys at R7or Glu at R2and Orn at R7and -71- 181632343.4Docket No.: 146316.8033.WO02 when R1is Arg, then R2is not Dap when Y1and Y2are present and R2is not Lys when R7is Asp; when R4is p(F)dPhe, then R3is Pro or absent, wherein when R3is absent, R1is not Arg when R2is Lys; when R4is dPhe and R3is Asn, then R1is Arg, R2is Dab, and Y1is dArg; and when R4is dPhe and R3is Pro, then the non-naturally occurring melanocortin analog is not cyclized through a lactam bond between Lys at R2and Glu at R7.

2. The non-naturally occurring melanocortin analog of claim 1, wherein: R1is selected from Nle, Arg, and dArg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3is absent, Pro, or Asn; R4is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, Lys, Orn; Y1is absent, dVal, or dArg; Y2is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2and Orn at R7; a lactam bridge between Glu at R2and Lys at R7; a lactam bridge between Asp at R2, R3at Asn, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Dap-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 25); -72- 181632343.4Docket No.: 146316.8033.WO02 Ac-Nle-c[Dab-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 26); Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27); Ac-Nle-c[Lys-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 28); Ac-Nle-c[Lys-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 29); Ac-Nle-c[Orn-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 30); Ac-Nle-c[Orn-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 31); Ac-Arg-c[Glu-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 189); Ac-Nle-c[Glu-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 190); Ac-Nle-c[Lys-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 196); Ac-Nle-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Arg-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 156); Ac-Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 149); Ac-Arg-c[Asp-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 172); Ac-Arg-c[Lys-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 197); Ac-Arg-c[Lys-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 195); Ac-Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 21); Ac-Nle-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 14); Ac-Nle-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 23); Ac-Nle-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 24); Ac-Nle-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-Nle-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 18); -73- 181632343.4Docket No.: 146316.8033.WO02 Ac-Nle-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Glu-Asn-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Glu-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Lys-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Nle-c[Lys-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 70); Ac-Nle-c[Orn-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-Nle-c[Orn-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 126); Ac-Arg-c[Asp-Asn-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 132); Ac-Arg-c[Asp-Asn-dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 133); Ac-Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 127); Ac-Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 128); Ac-Arg-c[Glu-Asn-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 134); Ac-Arg-c[Glu-Asn-dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 135); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 129); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 130); Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 131); Ac-Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 106); Ac-Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 112); Ac-Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 113); Ac-Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 114); Ac-Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 115); Ac-Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 109); Ac-Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 110); Ac-Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 111); Ac-Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 155); -74- 181632343.4Docket No.: 146316.8033.WO02 Ac-Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 148); Ac-Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 150); Ac-Arg-c[Glu-Asn-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 173); Ac-Arg-c[Glu-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 174); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 168); Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 170); Ac-Arg-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 108); Ac-Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 152); Ac-Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 154); Ac-Arg-c[Orn-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 171); Ac-Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 167); Ac-Arg-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 107); Ac-Arg-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 147); Ac-Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 22); Ac-Nle-c[Asp-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 151); Ac-Arg-c[Lys-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 169); Ac-Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 153); Ac-Nle-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 13); Ac-Nle-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Lys-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 67); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 119); Ac-Arg-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 146); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 158); -75- 181632343.4Docket No.: 146316.8033.WO02 Ac-Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 166); Ac-Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dArg-dVal-NH2 (SEQ ID NO: 186); Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 354); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 355); Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 356); and Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ D NO: 357).

3. The non-naturally occurring melanocortin analog of claim 1 or 2, wherein the sequence of Formula (I) is a sequence of Formula (IA): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IA), wherein: R1is Nle or Arg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3is Asn; R4is p(Cl)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, Lys, Orn; Y1is absent or dVal; Y2is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu or Asp at R2and Orn or Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7.

4. The non-naturally occurring melanocortin analog of claim 1 or 2, wherein the sequence of Formula (I) is a sequence of Formula (IB): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IB), wherein: -76- 181632343.4Docket No.: 146316.8033.WO02 R1is selected from Nle, Arg, and dArg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, and Glu; R3is absent or Pro; R4is p(F)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, and Lys; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu at R2and Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7.

5. The non-naturally occurring melanocortin analog of claim 1 or 2, wherein the sequence of Formula (I) is a sequence of Formula (IC): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IC), wherein: R1is Nle or Arg; R2is selected from the group consisting of Dap, Dab, Lys, Orn, and Glu; R3is absent, Pro, or Asn; R4is dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Glu, Asp, and Lys; Y1is dVal; Y2is dPro; and -77- 181632343.4Docket No.: 146316.8033.WO02 the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu at R2and Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2and Glu or Asp at R7.

6. The non-naturally occurring melanocortin analog of any one of claims 1-5, wherein the N-terminus is modified by an acyl group.

7. The non-naturally occurring melanocortin analog of claim 6, wherein the acyl group is acetyl group.

8. The non-naturally occurring melanocortin analog of any one of claims 1-7, wherein the N-terminus is modified by an amide group.

9. The non-naturally occurring melanocortin analog of any one of claims 1-8, wherein R4is p(F)dPhe.

10. The non-naturally occurring melanocortin analog of any one of claims 1-9, wherein R3is Pro.

11. The non-naturally occurring melanocortin analog of any one of claims 1-10, wherein R1is Nle.

12. The non-naturally occurring melanocortin analog of claim 11, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c[Dap-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 1); Ac-Nle-c[Dab-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 2); Ac-Nle-c[Lys-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-Nle-c[Lys-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 4); Ac-Nle-c[Orn-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 5); Ac-Nle-c[Orn-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 6); and -78- 181632343.4Docket No.: 146316.8033.WO02 Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 19), wherein c represents cyclization through R2and R7via a lactam bond.

13. The non-naturally occurring melanocortin analog of any one of claims 1-10, wherein R1is dArg.

14. The non-naturally occurring melanocortin analog of claim 13, wherein the sequence of Formula (I) is: Ac-dArg-c[Orn-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 203), wherein c represents cyclization through R2and R7via a lactam bond.

15. The non-naturally occurring melanocortin analog of any one of claims 1-8, wherein R4is p(Cl)dPhe.

16. The non-naturally occurring melanocortin analog of any one of claims 1-8 and 15, wherein R3is Asn.

17. The non-naturally occurring melanocortin analog of any one of claims 1-8, 15, and 16, wherein R1is Nle.

18. The non-naturally occurring melanocortin analog of claim 17, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 40); Ac-Nle-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 47), wherein c represents cyclization through R2and R7via a lactam bond.

19. The non-naturally occurring melanocortin analog of any one of claims 1-8, 15, and 16, wherein R1is Arg. -79- 181632343.4Docket No.: 146316.8033.WO02 20. The non-naturally occurring melanocortin analog of any one of claims 1-8, 15, 16, and 19, wherein Y1is dVal and Y2is dPro.

21. The non-naturally occurring melanocortin analog of claim 20, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Arg-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 157); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 159); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 160); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 161); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 162); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 163); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 164); and Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 165), wherein c represents cyclization through R2and R7via a lactam bond.

22. The non-naturally occurring melanocortin analog of any one of claims 1-8, 15, 16, and 19, wherein Y1and Y2are absent.

23. The non-naturally occurring melanocortin analog of claim 22, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 116); Ac-Arg-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 117); Ac-Arg-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 118); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 120); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 121); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 122); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 123); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 124); and -80- 181632343.4Docket No.: 146316.8033.WO02 Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 125), wherein c represents cyclization through R2and R7via a lactam bond.

24. The non-naturally occurring melanocortin analog of any one of claims 1-8, wherein R4is dPhe.

25. The non-naturally occurring melanocortin analog of any one of claims 1-8 and 24, wherein R3is Pro.

26. The non-naturally occurring melanocortin analog of any one of claims 1-8, 24, and 25, wherein R1is Nle.

27. The non-naturally occurring melanocortin analog of claim 26, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c[Dap-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Nle-c[Dab-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-Nle-c[Lys-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-Nle-c[Orn-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 59); Ac-Nle-c[Orn-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 60); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73), wherein c represents cyclization through R2and R7via a lactam bond.

28. The non-naturally occurring melanocortin analog of any one of claims 1-8 and 30, wherein R3is Asn.

29. The non-naturally occurring melanocortin analog of claim 28, wherein the sequence of Formula (I) is: Ac-Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dArg-dVal-NH2 (SEQ ID NO: 185), wherein c represents cyclization through R2and R7via a lactam bond.

30. The non-naturally occurring melanocortin analog of any one of claims 1-8, wherein R4is dPhe or p(F)dPhe. -81- 181632343.4Docket No.: 146316.8033.WO02 31. The non-naturally occurring melanocortin analog of any one of claims 1-8 and 30, wherein R3is absent.

32. The non-naturally occurring melanocortin analog of claim 31, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Arg-c[Glu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 187); Ac-Nle-c[Glu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 188); Ac-Arg-c[Glu-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 191); Ac-Nle-c[Glu-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 192); Ac-Arg-c[Lys-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 193); Ac-Nle-c[Lys-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 194); and Ac-Nle-c[Lys-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 198), wherein c represents cyclization through R2and R7via a lactam bond.

33. The non-naturally occurring melanocortin analog of any one of claims 1-32, wherein the sequence of Formula (I) is selected from the group consisting of SEQ ID NOs: 1-6, 19, 40, 42, 43, 47, 55-57, 59, 60, 73, 116-118, 120-125, 157, 159-165, 185, 187, 188, 191-194, 198, and 203.

34. The non-naturally occurring melanocortin analog of any one of claims 1-33, wherein the non-naturally occurring melanocortin analog is present in a composition.

35. The non-naturally occurring melanocortin analog of claim 34, wherein the composition further comprises a pharmaceutical salt.

36. The non-naturally occurring melanocortin analog of claim 34, wherein the composition further comprises a pharmaceutical carrier.

37. The non-naturally occurring melanocortin analog of claim 34, wherein the pharmaceutical carrier comprises water -82- 181632343.4Docket No.: 146316.8033.WO02 38. The non-naturally occurring melanocortin analog of claim 34, 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.

39. The non-naturally occurring melanocortin analog of claim 38, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (I)and 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.

40. The non-naturally occurring melanocortin analog of claim 39, 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.

41. The non-naturally occurring melanocortin analog of any one of claims 1-40, wherein the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

42. The non-naturally occurring melanocortin analog of any one of claims 34- 41, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally.

43. The non-naturally occurring melanocortin analog of any one of claims 34- 42, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.

44. The non-naturally occurring melanocortin analog of any one of claims 1-43, wherein the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of the subject.

45. The non-naturally occurring melanocortin analog of any one of claims 1-44, wherein the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.001 mg / kg to 25 mg / kg per body weight of the subject. -83- 181632343.4Docket No.: 146316.8033.WO02 46. The non-naturally occurring melanocortin analog of any one of claims 1-45, wherein the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.5 mg / kg to 10 mg / kg per body weight of the subject.

47. The non-naturally occurring melanocortin analog of any one of claims 1-46, 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 the subject.

48. The non-naturally occurring melanocortin analog of any one of claims 1-47, 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 the subject.

49. The non-naturally occurring melanocortin analog of any one of claims 1-48, wherein the non-naturally occurring melanocortin analog is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

50. The non-naturally occurring melanocortin analog of any one of claims 1-49, wherein the non-naturally occurring melanocortin analog is administered to the 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. -84- 181632343.4

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