Non-naturally occurring melanocortin analogs with an extended c-terminus for modulating weight loss

Abstract

The present technology comprises non-naturally occurring melanocortin analogs or pharmaceutically acceptable salts, solvates, or stereoisomers thereof and compositions comprising the same. The non-naturally occurring melanocortin analogs may be full agonists of the melanocortin 3 receptor and full or partial agonists of the melanocortin 4 receptor with sub-micromolar and / or low-nanomolar binding activity.

Description

Docket No.: 183B-412969-WONON-NATURALLY OCCURRING MELANOCORTIN ANALOGS WITH AN EXTENDED C-TERMINUS FOR MODULATING WEIGHT LOSSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 683,658, filed August 15, 2024; and U.S. Provisional Patent Application No. 63 / 683,666, filed August 15, 2024; each of which are incorporated herein by reference in their entirety.INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] This application contains an ST.26 compliant Sequence Listing, which is submitted concurrently in xml format and is hereby incorporated by reference in its entirety. The .xml copy, created on August 12, 2025, is titled “183B-412969-WO_SL.xml” and is 1 ,048,072 bytes in size.BACKGROUND

[0003] Melanocortins are a group of small peptides that bind to a family of five known melanocortin receptors (MC1 R 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 a-, p- and y-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 selectiveSMRH:4906-9094-6395 -1 -Docket No.: 183B-412969-WO melanocortin analogs in the treatment and prevention of various melanocortin-related diseases.SUMMARY

[0006] The present technology comprises non-naturally occurring melanocortin analogs and compositions comprising the same.

[0007] In some embodiments, the present technology comprises a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):R1- R2- R3- R4- R5- R6- R7- Y1- Y2- Y3- Y4-Y5( I ) , wherein:R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Orn, Dab, Aad, Asp, and Glu;Y1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;Y3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; andSMRH:4906-9094-6395 -2-Docket No.: 183B-412969-WO the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp, Aad, or Glu and R7is Lys, Dab, or Orn, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu; provided that: when Y1is dVal, then Y2is dPro.

[0008] In some embodiments,R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Orn, Dab, Aad, Asp, and Glu;Y1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;Y3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp, Aad, or Glu and R7is Lys, Dab, or Orn, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu;SMRH:4906-9094-6395 -3-Docket No.: 183B-412969-WO provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 2);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 3);Ac-Nle-c[Glu-His-dPhe-Arg-Trp-Orn]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 4);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 5);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Nle-c[Orn-His-dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 8);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 9);Ac-Nle-c[Dab-His-dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 10);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 11 );Ac-Nle-c[Aad-His-dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 12); andAc-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 13), wherein c represents cyclization through a lactam bond between R2and R7.

[0009] In some embodiments, the sequence of Formula (I) is a sequence of Formula (IA):R1- R2- R3- R4- R5- R6- R7- Y1- Y2-Y3-Y4- Y5( I A) , wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is Orn;SMRH:4906-9094-6395 -4-Docket No.: 183B-412969-WOY1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;Y3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp, Aad, or Glu and R7is Lys, Dab, or Orn, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu; provided that: when Y1is dVal, then Y2is dPro.

[0010] In some embodiments,R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is Orn;Y1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;SMRH:4906-9094-6395 -5-Docket No.: 183B-412969-WOY3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 5), wherein c represents cyclization through a lactam bond between R2and R7.

[0011] In some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (IA(i)):R1- R2- R3- R4- R5- R6- R7-Y1-Y2-Y3-Y4-Y5( I A(i ) ) , wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is D-valine (dVal);Y2is D-proline (dPro);Y3is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), Asp, oc-phenylglycine (Phg), D-oc-phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y4is absent or is selected from the group consisting of dSer, dPhe, Phg, dPhg, Asp, Orn, dOrn, dAsp, dNIe, dAla, and Gly;SMRH:4906-9094-6395 -6-Docket No.: 183B-412969-WOY5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0012] In some embodiments,R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is D-valine (dVal);Y2is D-proline (dPro);Y3is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), D-alanine (dAla), and glycine (Gly);Y4is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, dAla, and Gly;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0013] In some embodiments,R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);SMRH:4906-9094-6395 -7-Docket No.: 183B-412969-WOR7is ornithine (Orn);Y1is D-valine (dVal);Y2is D-proline (dPro);Y3is selected from the group consisting of Asp, oc-phenylglycine (Phg), D-oc- phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y4is absent or is selected from the group consisting of Phg, dPhg, Asp, and Orn;Y5is absent; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0014] In some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (IA(ii)) :R1- R2- R3- R4- R5- R6- R7- Y1- Y2- Y3-Y4- Y5( I A ( i i ) ) , wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), Asp, oc-phenylglycine (Phg), D-oc-phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-valine (dVal), dSer, dPhe, dOrn, dAsp, dNIe, Asp, Phg, dPhg, Orn, dAla, and Gly;Y3is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, dOrn, dAsp, dNIe, Asp, Phg, dPhg, and Orn;Y4is absent, dPro, or dVal;Y5is absent or dPro; andSMRH:4906-9094-6395 -8-Docket No.: 183B-412969-WO the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0015] In some embodiments,R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-valine (dVal), dSer, dPhe, dOrn, dAsp, dNIe, dAla, and Gly;Y3is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, dOrn, dAsp, and dNIe;Y4is absent, dPro, or dVal;Y5is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0016] In some embodiments,R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);SMRH:4906-9094-6395 -9-Docket No.: 183B-412969-WOY1is selected from the group consisting of Asp, oc-phenylglycine (Phg), D-oc- phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-valine (dVal), Asp, Phg, dPhg, Orn, dAla, and Gly;Y3is selected from the group consisting of D-proline (dPro), dVal, Asp, Phg, dPhg, and Orn;Y4is absent, dPro, or dVal;Y5is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0017] In some embodiments, the sequence of Formula (I) is a sequence of Formula (IB):R1- R2- R3- R4- R5- R6- R7- Y1- Y2-Y3-Y4- Y5(IB), wherein:R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Dab, Aad, Asp, and glutamic acid (Glu);Y1is selected from the group consisting of D-valine (dVal), D-ornithine (dOrn), D- alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dOrn, dAla, and Gly;Y3is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y4is absent or is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;SMRH:4906-9094-6395 -10-Docket No.: 183B-412969-WOY5is absent, dOrn, or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp or Aad and R7is Lys or Dab, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu, provided that: when Y1is dVal, then Y2is dPro.

[0018] In some embodiments,R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Dab, Aad, Asp, and glutamic acid (Glu);Y1is selected from the group consisting of D-valine (dVal), D-ornithine (dOrn), D- alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dOrn, dAla, and Gly;Y3is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y4is absent or is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y5is absent, dOrn, or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp or Aad and R7is Lys or Dab, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:SMRH:4906-9094-6395 -11 -Docket No.: 183B-412969-WOAc-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 2);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 3);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Nle-c[Orn-His-dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 8);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 9);Ac-Nle-c[Dab-His-dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 10);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 11 );Ac-Nle-c[Aad-His-dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 12); andAc-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 13), wherein c represents cyclization through a lactam bond between R2and R7.

[0019] In some embodiments, the N-terminus of the sequence of any one of Formulae (l)-(IB) is acylated.

[0020] In some embodiments, the N-terminus of the sequence of any one of Formulae (l)-(IB) is acetylated.

[0021] In some embodiments, the N-terminus of the sequence of any one of Formulae (l)-(IB) is not modified.

[0022] In some embodiments, the C-terminus of the sequence of any one of Formulae (l)-(IB) is amidated.

[0023] In some embodiments, the C-terminus of the sequence of any one of Formulae (l)-(IB) is not modified.

[0024] In some embodiments, the sequence of Formula (I) is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0025] In some embodiments, Y1is dVal; and Y2is dPro.

[0026] In some embodiments, Y4and Y5are absent.SMRH:4906-9094-6395 -12-Docket No.: 183B-412969-WO

[0027] In some embodiments, Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0028] In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-NH2(SEQ ID NO: 14);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-NH2(SEQ ID NO: 15);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-NH2(SEQ ID NO: 16);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-NH2(SEQ ID NO: 17); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-NH2(SEQ ID NO: 18), wherein c represents cyclization through R2and R7via a lactam bond.

[0029] In some embodiments, Y3is selected from the group consisting of Phg, dPhg, Asp, and Orn.

[0030] In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Phg-NH2(SEQ ID NO: 19);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhg-NH2(SEQ ID NO: 20);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Asp-NH2(SEQ ID NO: 21 ); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Orn-NH2(SEQ ID NO: 22), wherein c represents cyclization through R2and R7via a lactam bond.

[0031] In some embodiments, Y3is dAla or Gly; and Y5is absent.

[0032] In some embodiments, Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0033] In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-NH2(SEQ ID NO: 23);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-NH2(SEQ ID NO: 24);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 25); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-NH2(SEQ ID NO: 26); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-NH2(SEQ ID NO: 27);SMRH:4906-9094-6395 -13-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dSer-NH2 (SEQ ID NO: 28);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dPhe-NH2(SEQ ID NO: 29);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dOrn-NH2 (SEQ ID NO: 30);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dAsp-NH2 (SEQ ID NO: 31 ); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dNle-NH2 (SEQ ID NO: 32), wherein c represents cyclization through R2and R7via a lactam bond.

[0034] In some embodiments, Y4is selected from the group consisting of Phg, dPhg, Asp, and Orn.

[0035] In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-Phg-NH2(SEQ ID NO: 33);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhg-NH2(SEQ ID NO: 34);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-Asp-NH2(SEQ ID NO: 35);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-Orn-NH2 (SEQ ID NO: 36);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Phg-NH2(SEQ ID NO: 37);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dPhg-NH2(SEQ ID NO: 38);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Asp-NH2(SEQ ID NO: 39); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Orn-NH2 (SEQ ID NO: 40), wherein c represents cyclization through R2and R7via a lactam bond.

[0036] In some embodiments, Y3is dAla or Gly; and Y4is dAla or Gly.

[0037] In some embodiments, Y5is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0038] In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dSer-NH2(SEQ ID NO: 66);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dPhe-NH2(SEQ ID NO: 67);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dOrn-NH2 (SEQ ID NO: 68); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dAsp-NH2(SEQ ID NO: 69); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dNle-NH2(SEQ ID NO: 70);SMRH:4906-9094-6395 -14-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dSer-NH2 (SEQ ID NO: 71 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dPhe-NH2(SEQ ID NO: 72);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dOrn-NH2 (SEQ ID NO: 73);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dAsp-NH2 (SEQ ID NO: 74); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dNle-NH2 (SEQ ID NO: 75), wherein c represents cyclization through R2and R7via a lactam bond.

[0039] In some embodiments, Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0040] In some embodiments, Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe; and Y5is absent.

[0041] In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dSer-NH2(SEQ ID NO: 41 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dPhe-NH2(SEQ ID NO: 42);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dOrn-NH2 (SEQ ID NO: 43);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dAsp-NH2(SEQ ID NO: 44);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dNle-NH2(SEQ ID NO: 45);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dSer-NH2(SEQ ID NO: 46);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dPhe-NH2(SEQ ID NO: 47);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dOrn-NH2 (SEQ ID NO: 48);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dAsp-NH2(SEQ ID NO: 49);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dNle-NH2(SEQ ID NO: 50);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dSer-NH2 (SEQ ID NO: 51 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dPhe-NH2 (SEQ ID NO: 52);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dOrn-NH2 (SEQ ID NO: 53);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dAsp-NH2 (SEQ ID NO: 54);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dNle-NH2 (SEQ ID NO: 55);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dSer-NH2(SEQ ID NO: 56);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dPhe-NH2(SEQ ID NO: 57);SMRH:4906-9094-6395 -15-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dOrn-NH2(SEQ ID NO: 58);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dAsp-NH2(SEQ ID NO: 59);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dNle-NH2(SEQ ID NO: 60);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dSer-NH2(SEQ ID NO: 61 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dPhe-NH2(SEQ ID NO: 62);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dOrn-NH2(SEQ ID NO: 63);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dAsp-NH2(SEQ ID NO: 64); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dNle-NH2(SEQ ID NO: 65), wherein c represents cyclization through R2and R7via a lactam bond.

[0042] In some embodiments,Y3is dAla; andY5is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0043] In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dSer-NH2(SEQ ID NO: 76);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dPhe-NH2(SEQ ID NO: 77);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dOrn-NH2(SEQ ID NO: 78);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dAsp-NH2(SEQ ID NO: 79);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dNle-NH2(SEQ ID NO: 80); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dSer-NH2(SEQ ID NO: 81 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dPhe-NH2(SEQ ID NO:82);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dOrn-NH2(SEQ ID NO:83);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dAsp-NH2(SEQ ID NO:84);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dNle-NH2(SEQ ID NO: 85);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dSer-NH2(SEQ ID NO: 86); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dPhe-NH2(SEQ ID NO: 87);SMRH:4906-9094-6395 -16-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dOrn-NH2 (SEQ ID NO: 88);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dAsp-NH2(SEQ ID NO:184);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dNle-NH2 (SEQ ID NO:185);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dSer-NH2 (SEQ ID NO:186);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dPhe-NH2 (SEQ ID NO:187);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dOrn-NH2 (SEQ ID NO:188);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dAsp-NH2 (SEQ ID NO:189);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dNle-NH2 (SEQ ID NO:190);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dSer-NH2 (SEQ ID NO:191 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dPhe-NH2 (SEQ ID NO:192);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dOrn-NH2 (SEQ ID NO:193);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dAsp-NH2 (SEQ ID NO:194); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dNle-NH2 (SEQ ID NO:195), wherein c represents cyclization through R2and R7via a lactam bond.

[0044] In some embodiments, Y2is dVal; Y3is dPro; and Y4and Y5are absent.

[0045] In some embodiments, Y1is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.SMRH:4906-9094-6395 -17-Docket No.: 183B-412969-WO

[0046] In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dVal-dPro-NH2 (SEQ ID NO: 89);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dVal-dPro-NH2(SEQ ID NO: 90);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Om]-dOrn-dVal-dPro-NH2(SEQ ID NO: 91 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dVal-dPro-NH2(SEQ ID NO: 92); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dVal-dPro-NH2(SEQ ID NO: 93), wherein c represents cyclization through R2and R7via a lactam bond.

[0047] In some embodiments, Y1is selected from the group consisting of Phg, dPhg, Asp, and Orn.

[0048] In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Phg-dVal-dPro-NH2(SEQ ID NO: 94);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhg-dVal-dPro-NH2(SEQ ID NO: 95);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Asp-dVal-dPro-NH2(SEQ ID NO: 96); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Orn-dVal-dPro-NH2 (SEQ ID NO: 97), wherein c represents cyclization through R2and R7via a lactam bond.

[0049] In some embodiments, Y3is dVal; and Y4is dPro.

[0050] In some embodiments, Y2is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0051] In some embodiments, Y1is dAla or Gly.

[0052] In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dVal-dPro-NH2(SEQ ID NO: 98);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dVal-dPro-NH2(SEQ ID NO: 99);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dVal-dPro-NH2 (SEQ ID NO: 100);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 101 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dVal-dPro-NH2(SEQ ID NO: 102); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dSer-dVal-dPro-NH2(SEQ ID NO: 103);SMRH:4906-9094-6395 -18-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dPhe-dVal-dPro-NH2(SEQ ID NO: 104);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 105);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 106); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dNle-dVal-dPro-NH2(SEQ ID NO: 107), wherein c represents cyclization through R2and R7via a lactam bond.

[0053] In some embodiments, Y1is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0054] In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dSer-dVal-dPro-NH2(SEQ ID NO: 116);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dPhe-dVal-dPro-NH2(SEQ ID NO: 1 17);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dOrn-dVal-dPro-NH2(SEQ ID NO: 118);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dAsp-dVal-dPro-NH2(SEQ ID NO: 1 19);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dNle-dVal-dPro-NH2(SEQ ID NO: 120);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dSer-dVal-dPro-NH2(SEQ ID NO: 121 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dPhe-dVal-dPro-NH2(SEQ ID NO: 122);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dOrn-dVal-dPro-NH2(SEQ ID NO: 123);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dAsp-dVal-dPro-NH2(SEQ ID NO: 124);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dNle-dVal-dPro-NH2(SEQ ID NO: 125);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dSer-dVal-dPro-NH2(SEQ ID NO: 126);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dPhe-dVal-dPro-NH2(SEQ ID NO: 127);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dOrn-dVal-dPro-NH2(SEQ ID NO: 128);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dAsp-dVal-dPro-NH2(SEQ ID NO: 129);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dNle-dVal-dPro-NH2(SEQ ID NO: 130);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dSer-dVal-dPro-NH2(SEQ ID NO: 131 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dPhe-dVal-dPro-NH2(SEQ ID NO: 132);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dOrn-dVal-dPro-NH2(SEQ ID NO: 133);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dAsp-dVal-dPro-NH2(SEQ ID NO: 134); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dNle-dVal-dPro-NH2(SEQ ID NO: 135); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dSer-dVal-dPro-NH2(SEQ ID NO: 136);SMRH:4906-9094-6395 -19-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dPhe-dVal-dPro-NH2(SEQ ID NO: 137);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dOrn-dVal-dPro-NH2(SEQ ID NO: 138);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dAsp-dVal-dPro-NH2(SEQ ID NO: 139); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dNle-dVal-dPro-NH2(SEQ ID NO: 140), wherein c represents cyclization through R2and R7via a lactam bond.

[0055] In some embodiments, Y2is selected from the group consisting of Phg, dPhg, Asp, and Orn.

[0056] In some embodiments, Y1is dAla or Gly.

[0057] In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-Phg-dVal-dPro-NH2(SEQ ID NO: 108);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhg-dVal-dPro-NH2(SEQ ID NO: 109);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Phg-dVal-dPro-NH2(SEQ ID NO: 1 10);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dPhg-dVal-dPro-NH2(SEQ ID NO: 111 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-Asp-dVal-dPro-NH2(SEQ ID NO: 112);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Asp-dVal-dPro-NH2(SEQ ID NO: 1 13);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-Orn-dVal-dPro-NH2(SEQ ID NO: 114); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Orn-dVal-dPro-NH2(SEQ ID NO: 115), wherein c represents cyclization through R2and R7via a lactam bond.

[0058] In some embodiments, Y4is dVal; and Y5is dPro.

[0059] In some embodiments, Y1is dAla or Gly.

[0060] In some embodiments, Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0061] In some embodiments, Y2is dAla and Gly.

[0062] In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dSer-dVal-dPro-NH2(SEQ ID NO: 141 );SMRH:4906-9094-6395 -20-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dPhe-dVal-dPro-NH2(SEQ ID NO:142);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO:143);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO:144);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dNle-dVal-dPro-NH2(SEQ ID NO:145);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dSer-dVal-dPro-NH2(SEQ ID NO: 146);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dPhe-dVal-dPro-NH2(SEQ ID NO: 147);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 148);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 149); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dNle-dVal-dPro-NH2(SEQ ID NO: 150), wherein c represents cyclization through R2and R7via a lactam bond.

[0063] In some embodiments, Y2is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0064] In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dSer-dVal-dPro-NH2(SEQ ID NO:159);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dPhe-dVal-dPro-NH2(SEQ ID NO:160);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dOrn-dVal-dPro-NH2(SEQ ID NO:161 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dAsp-dVal-dPro-NH2(SEQ ID NO:162);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dNle-dVal-dPro-NH2(SEQ ID NO:163);SMRH:4906-9094-6395 -21 -Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dSer-dVal-dPro-NH2 (SEQ ID NO:164);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dPhe-dVal-dPro-NH2(SEQ ID NO:165);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dOrn-dVal-dPro-NH2 (SEQ ID NO:166);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dAsp-dVal-dPro-NH2 (SEQ ID NO:167);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dNle-dVal-dPro-NH2 (SEQ ID NO:168);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dSer-dVal-dPro-NH2 (SEQ ID NO:169);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dPhe-dVal-dPro-NH2 (SEQ ID NO:1 0);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dOrn-dVal-dPro-NH2 (SEQ ID NO:171 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dAsp-dVal-dPro-NH2 (SEQ ID NO:172);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dNle-dVal-dPro-NH2 (SEQ ID NO:173);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dSer-dVal-dPro-NH2 (SEQ ID NO:174);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dPhe-dVal-dPro-NH2 (SEQ ID NO:175);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dOrn-dVal-dPro-NH2 (SEQ ID NO:176);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dAsp-dVal-dPro-NH2 (SEQ ID NO:177);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dNle-dVal-dPro-NH2 (SEQ ID NO:178);SMRH:4906-9094-6395 -22-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dSer-dVal-dPro-NH2 (SEQ ID NO:179);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dPhe-dVal-dPro-NH2(SEQ ID NO:180);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dOrn-dVal-dPro-NH2 (SEQ ID NO:181 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dAsp-dVal-dPro-NH2 (SEQ ID NO:182); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dNle-dVal-dPro-NH2 (SEQ ID NO:183), wherein c represents cyclization through R2and R7via a lactam bond.

[0065] In some embodiments, Y3is selected from the group consisting of Phg, dPhg, Asp, and Orn.

[0066] In some embodiments, Y2is dAla and Gly.

[0067] In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-Phg-dVal-dPro-NH2(SEQ ID NO: 151 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dPhg-dVal-dPro-NH2(SEQ ID NO: 152);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-Phg-dVal-dPro-NH2(SEQ ID NO: 153);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dPhg-dVal-dPro-NH2(SEQ ID NO: 154);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-Asp-dVal-dPro-NH2(SEQ ID NO: 155);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-Asp-dVal-dPro-NH2(SEQ ID NO: 156);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-Orn-dVal-dPro-NH2 (SEQ ID NO: 157); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-Orn-dVal-dPro-NH2 (SEQ ID NO: 158), wherein c represents cyclization through R2and R7via a lactam bond.

[0068] In some embodiments, the sequence of Formula (I) or (IB) is cyclized via a lactam bond between Orn at R2and Glu at R7.SMRH:4906-9094-6395 -23-Docket No.: 183B-412969-WO

[0069] In some embodiments, the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dOrn-dVal-dPro-NH2 (SEQ ID NO: 230);Ac-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 231 );Ac-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 232);Ac-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 233);Ac-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 234);Ac-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-dOrn-NH2(SEQ ID NO: 235);Ac-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 236);Ac-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 237);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 238); andAc-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 239), wherein c represents cyclization through R2and R7via a lactam bond.

[0070] In some embodiments, the sequence of Formula (I) or (IB) is cyclized via a lactam bond between Asp at R2and Lys at R7.

[0071] In some embodiments, R4is p(F)dPhe.

[0072] In some embodiments, the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dOrn-dVal-dPro-NH2(SEQ ID NO: 200);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 201 );Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 202);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 203);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 204);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-dOrn-NH2(SEQ ID NO: 205);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 206);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 207);SMRH:4906-9094-6395 -24-Docket No.: 183B-412969-WOAc-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dAla-dOrn-NH2 (SEQ ID NO: 208); andAc-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 209), wherein c represents cyclization through R2and R7via a lactam bond.

[0073] In some embodiments, R4is dPhe.

[0074] In some embodiments, the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAsp-dVal-dPro-NH2 (SEQ ID NO: 196);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dOrn-dVal-dPro-NH2(SEQ ID NO: 197);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dAsp-dVal-dPro-NH2 (SEQ ID NO: 198);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dOrn-dVal-dPro-NH2 (SEQ ID NO: 199);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 250);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 251 );Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 252);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 253);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 254);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 255);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dAsp-NH2 (SEQ ID NO: 256);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dOrn-NH2(SEQ ID NO: 257);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dAsp-NH2 (SEQ ID NO: 258);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 259);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-dAsp-NH2 (SEQ ID NO: 260); and Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 261 ); wherein c represents cyclization through R2and R7via a lactam bond.

[0075] In some embodiments, the sequence of Formula (I) or (IB) is cyclized via a lactam bond between Lys at R2and Asp at R7.

[0076] In some embodiments, R4is p(F)dPhe.

[0077] In some embodiments, the sequence of Formula (I) or (IB) is selected from the group consisting of:SMRH:4906-9094-6395 -25-Docket No.: 183B-412969-WOAc-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dOrn-dVal-dPro-NH2(SEQ ID NO: 220);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 221 );Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 222);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 223);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 224);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-dOrn-NH2(SEQ ID NO: 225);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 226);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 227);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 228); andAc-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 229), wherein c represents cyclization through R2and R7via a lactam bond.

[0078] In some embodiments, R4is dPhe.

[0079] In some embodiments, the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAsp-dVal-dPro-NH2(SEQ ID NO: 262);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dOrn-dVal-dPro-NH2(SEQ ID NO: 263);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 264);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 265);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 266);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 267);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 268);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 269);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 270);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 271 );Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dAsp-NH2(SEQ ID NO: 272);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dOrn-NH2(SEQ ID NO: 273);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dAsp-NH2(SEQ ID NO: 274);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 275);SMRH:4906-9094-6395 -26-Docket No.: 183B-412969-WOAc-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-dAsp-NH2 (SEQ ID NO: 276); and Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 277), wherein c represents cyclization through R2and R7via a lactam bond.

[0080] In some embodiments, the sequence of Formula (I) or (IB) is cyclized via a lactam bond between Aad at R2and Dab at R7.

[0081] In some embodiments, the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dOrn-dVal-dPro-NH2(SEQ ID NO: 210);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 211 ); Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 212);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 213);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 214); Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-dOrn-NH2(SEQ ID NO: 215);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 216); Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 217);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 218); andAc-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 219), wherein c represents cyclization through R2and R7via a lactam bond.

[0082] In some embodiments, the sequence of Formula (I) or (IB) is cyclized via a lactam bond between Dab at R2and Aad at R7.

[0083] In some embodiments, the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dOrn-dVal-dPro-NH2(SEQ ID NO: 240); Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 241 ); Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 242);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 243);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 244);SMRH:4906-9094-6395 -27-Docket No.: 183B-412969-WOAc-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-dOrn-NH2(SEQ ID NO: 245); Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 246); Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 247);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 248); andAc-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 249), wherein c represents cyclization through R2and R7via a lactam bond.

[0084] In some embodiments, the non-naturally occurring melanocortin analog is present in a pharmaceutical composition.

[0085] In some embodiments, the pharmaceutical composition further comprises a pharmaceutical salt.

[0086] In some embodiments, the pharmaceutical composition further comprises a pharmaceutical carrier.

[0087] In some embodiments, the pharmaceutical carrier comprises water.

[0088] 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.

[0089] In some embodiments, the non-naturally occurring melanocortin analog is present in the composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the composition.

[0090] 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.

[0091] In some embodiments, the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

[0092] In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally.SMRH:4906-9094-6395 -28-Docket No.: 183B-412969-WO

[0093] In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.

[0094] In some embodiments, the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of the subject.

[0095] In some embodiments, 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.

[0096] In some embodiments, 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.

[0097] In some embodiments, the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

[0098] In some embodiments, 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.

[0099] In some embodiments, 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.

[0100] In some embodiments, 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.DETAILED DESCRIPTION

[0101] The present technology provides non-naturally occurring melanocortin analogs and pharmaceutically acceptable salts, solvates, and stereoisomers thereof, referred to herein collectively as melanocortin analogs. The melanocortin analogs of the present technology may selectively bind the melanocortin 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 theSMRH:4906-9094-6395 -29-Docket No.: 183B-412969-WO melanocortin 4 receptor. Certain melanocortin analogs bind the melanocortin 3 receptor with the same or generally similar affinity as the melanocortin 4 receptor.

[0102] Each of the melanocortin analogs may have one or more beta hairpin (p-hairpin) and / or beta turn (p-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 betaturns.

[0103] 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. In some embodiments, the melanocortin analogs have an extended C-terminus. For example, melanocortin analogs of the present technology may have one C-terminal residue, two C- terminal residues, three C-terminal residues, four C-terminal residues, or five C-terminal residues. A C-terminal extension may stabilize the melanocortin analogs against biodegradation and / or provide enhanced transport through the blood-brain-barrier the epithelium, or the gastrointestinal tract. The melanocortin analogs may be linear or cyclized.

[0104] The following description is merely exemplary in nature and is not intended to limit the present technology, its applications, or its uses. The description of specific examples indicated in various embodiments of the present technology are intended for purposes of illustration only and are not intended to limit the scope of the present technology disclosed herein. Moreover, recitation of multiple embodiments having stated features is not intended to exclude other embodiments having additional features or other embodiments incorporating different combinations of the stated features.

[0105] While the embodiments are described in sufficient detail to enable those skilled in the art to practice the present technology, it should be understood that other embodiments may be realized, and that logical changes may be made without departing from the spirit and scope of the present technology. Thus, the detailed description herein is presented for purposes of illustration only and not of limitation. For example, steps recited in any method or process may be executed in any order and are not limited to the order presented.SMRH:4906-9094-6395 -30-Docket No.: 183B-412969-WOMoreover, any of the steps thereof may be outsourced to or performed by one or more third parties.Definitions

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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 formulationsSMRH:4906-9094-6395 -31 -Docket No.: 183B-412969-WO containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21 st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005, which is incorporated herein by reference in its entirety). Some examples of physiologically acceptable carriers include antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and 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.

[0111] “Melanocortin analogs,” “melanocortin peptides,” or “melanocortins,” are used interchangeably and refer to melanocortin-receptor ligands, which are macromolecules containing at least one melanocortin pharmacophore. Melanocortin analogs are typically peptides that bind melanocortin receptors under physiological conditions. Melanocortin analogs include non-naturally occurring melanocortin peptides and truncated and / or modified versions of melanocortin full-length protein or peptides. For example, the full-length pro-opiomelanocortin protein (POMC), prior to proteolytic cleavage of “sub-peptides,” consists of 241 amino acids. Tissue-specific proteolytic cleavage of POMC yields peptides ranging in size from 13 amino acids to 76 amino acids. See Bicknell and Lawry, Encyclopedia of Stress, vol. 3, 257-265, Academic Press (2000). Synthesized, non- naturally occurring melanocortin analogs having increased melanocortin receptor activity as discussed herein are approximately 7-12 amino acids in size. Melanocortin analogs exhibit binding functionality with melanocortin receptors. In addition to peptides, the melanocortin analogs include small molecule analogs of melanocortin or portions thereof comprised of organic compounds, inorganic compounds, or combinations of peptide and small molecule — i.e., peptide mimetics, or various combinations thereof. “Melanocortin peptides”SMRH:4906-9094-6395 -32-Docket No.: 183B-412969-WO 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: 1 ) or a modified version thereof, or a structural or functional peptide mimetic thereof.

[0112] A “pharmacophore” is the minimum set of amino acid residues necessary to achieve a physiological effect; or a small molecule that is (with respect to a receptor) a structural mimic of the amino acid residues required for binding to and activation of a receptor. His-Phe-Arg-Trp (SEQ ID NO: 1 ) and their analogs are the pharmacophore of melanocortin for the regulated physiological effect. Therefore, non-naturally occurring melanocortin pharmacophore analogs can be small peptides or organic molecules designed to mimic the appearance or function (including activation or deactivation of receptor activity) of the melanocortin pharmacophore core sequence peptide.

[0113] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating and the like.

[0114] 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.

[0115] 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”SMRH:4906-9094-6395 -33-Docket No.: 183B-412969-WO includes peptides containing a variable number of amino acid residues, optionally with nonamino acid residue groups at the N- and C-termini, such groups including acyl, acetyl, alkenyl, alkyl, N-alkyl, amine, or amide groups, among others.

[0116] 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.

[0117] “Amino acids” are molecules containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen and have the generic formula H2N — CHR — COOH, wherein R represents a side chain group. The various a-amino acids differ in the side-chain moiety that is attached to the a-carbon. The “amino acids” of the present technology include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviation. See generally Synthetic Peptides: A User’s Guide, G. A. Grant, editor, W.H. Freeman & Co., New York (1992), the teachings of which are incorporated herein by reference, including the text and table set forth at pages 11 through 24. As set forth above, the term “amino acid” also includes stereoisomers and modifications of naturally occurring protein amino acids, nonprotein 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.

[0118] 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-proteinSMRH:4906-9094-6395 -34-Docket No.: 183B-412969-WO 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.

[0119] 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.

[0120] 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; “Gin” is glutamine; “Glu” is glutamic acid; “His” is histidine; “lie” is isoleucine; “Leu” is leucine; “Lys” is lysine; “Met” is methionine; “Phe” is phenylalanine; “Pro” is proline; “Ser” is serine; Thr is threonine; “Trp” is tryptophan; “Tyr” is tryosine; and “Vai” is valine. Unless otherwise indicated, all amino acids abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof can be used. Thus, for example, “L-Phe” or “IPhe” is L-phenylalanine; “D-Phe” or “dPhe” is D- phenylalanine; dVal is D-valine; dPro is D-proline; “D- / L-Phe” or “d / IPhe” is D-phenylalanine, L-phenylalanine, or combinations thereof; “Phe” is also D-phenylalanine, L-phenylalanine, or combinations thereof, and so on.

[0121] An alpha (oc)-amino acid has the generic formula H2N — CaHR — COOH, where R is a side chain moiety and the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (i.e., the oc-carbon). Other types of amino acids exist when the amino group is attached to a different carbon atom.

[0122] When p-amino acids are incorporated into peptides, two main types of p- peptides exist: those with the side chain residue, R, on the carbon next to the amine are called p3peptides and those with the side chain residue on the carbon next to the carbonylSMRH:4906-9094-6395 -35-Docket No.: 183B-412969-WO group are called p2amino acids. Further, p-amino acids may adopt L- or D- stereochemistry. Unless otherwise indicated, all p-amino acid abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof.

[0123] Gamma (y)-amino acids are amino acids with the carbon atom to which the amino group attaches is separated from the carboxylate moiety by two carbon atoms.

[0124] 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.

[0125] Additional abbreviations are used as follows: Orn is ornithine; dOrn is D- ornithing; Dab is 2,4-diaminobutyric acid; dDab is 2,4-D-diaminobutyric acid; Dap is 2,3- diaminopropionic acid; dDap is 2,3-D-diaminopropionic acid; Aad is aminoadipic acid; Phg is phenylglycine; dPhg is D-phenylglycine; Pen is Penicillamine; dPen is D-Penicillamine; and p(F)dPhe is para-fluoro-D-phenylalanine (I - iodo, Br - bromo, Cl - chloro, CF3 - trifluoromethyl).

[0126] 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.”

[0127] 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.

[0128] An “amine” includes compounds that contain an amine group ( — NH2).

[0129] 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.

[0130] Amino acids, including stereoisomers and modifications of naturally occurring amino acids, protein amino acids, non-protein amino acids, post-translationally modifiedSMRH:4906-9094-6395 -36-Docket No.: 183B-412969-WO 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.”

[0131] “Substantial degradation” refers to the degradation of the N-terminal extension, the C-terminal extension, both N- and C-terminal degradation or degradation to other regions of the melanocortin peptide by physiological enzymes and other factors, in such a manner or to a degree that side effects appear. According to one aspect, a melanocortin analog having a C-terminal extension that resists substantial degradation is one where no more than 50% of the administered peptide causes side effects and / or displays a low half-life. In some embodiments, no more than 25% of the administered peptide causes side effects and / or displays a low half-life. More preferably, in some embodiments, less than 10% of the administered peptide causes side effects and / or displays a low half-life, as compared to a melanocortin analog that lacks a C-terminal extension.

[0132] 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 and PCT Publication No. WO2025 / 123051 .Non-naturally Occurring Melanocortin Analogs

[0133] Non-naturally occurring melanocortin analogs described herein may be selective for the melanocortin 3 receptor and / or melanocortin 4 receptor over other melanocortin receptors, i.e., 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. Certain melanocortin analogs bind the melanocortin 3 receptor with the same or generally similar affinity as the melanocortin 4 receptor.

[0134] The non-naturally occurring melanocortin analogs of the present technology may be full agonists for one or more melanocortin receptors. A full agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect (Emax) agonist value of greater than or equal to 80%.SMRH:4906-9094-6395 -37-Docket No.: 183B-412969-WO

[0135] The non-naturally occurring melanocortin analogs of the present technology may be partial agonists or partial antagonists of one or more melanocortin receptor. A partial agonist or antagonist may comprise a non-naturally occurring melanocortin analog having a maximum effect Emax agonist value of less than 80%.

[0136] 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). Similarly, 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).

[0137] The non-naturally occurring melanocortin analogs of the present technology may be one or more of (i) a full MC3R agonist and a full MC4R agonist; (ii) a full MC3R agonist and a partial MC4R agonist; (iii) a full MC3R agonist having no MC4R agonist or antagonist activity; or (iv) a full MC3R agonist and a partial MC4R antagonist.

[0138] The non-naturally occurring melanocortin analogs in accordance with the present technology may have structural features that impart specific properties on the analogs, such as, for example, degradation resistance, enhanced epithelial, gastrointestinal, and / or blood brain barrier transport, and binding affinity for the MC4R and / or MC3R. For example, in some embodiments, the non-naturally occurring melanocortin analogs comprise one or more of (i) blood brain barrier passage capabilities, (ii) enhanced epithelial and / or gastrointestinal transport; (iii) degradation resistance; or (iv) equipotency on MC3R and MC4R activity. In some embodiments, the non-naturally occurring melanocortin analogs comprise two or more of (i)-(iv). In some embodiments, the non-naturally occurring melanocortin analogs comprise each of (i)-(iv). Accordingly, in some embodiments, the melanocortin analogs include a stabilizing N-terminus, and / or a C-terminus that provides enhanced transport of the analog. In some embodiments, melanocortin analogs include a D-valine-D-proline (dVal-dPro) chain as their C-terminus, which may provide enhanced transport and resistance to degradation Additionally, in some embodiments, the melanocortin analogs have one or more beta hairpin (p-hairpin) and / or beta turn (p-turn) structures. In general, cyclization and D-amino acids may induce and / or stabilize beta-turns..SMRH:4906-9094-6395 -38-Docket No.: 183B-412969-WO

[0139] 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 the R4position may be full agonists on MC4R. Further, inclusion of His at the R3position may result in full agonism on MC3R as well. By contrast, inclusion of residues other than His at the R3position, such as, for example, Pro, may decrease activity on the melanocortin 3 receptor, resulting in only partial agonism on MC3R.

[0140] 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- Y3- Y4-Y5( I ) , wherein:R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Orn, Dab, Aad, Asp, and Glu;Y1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;Y3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;SMRH:4906-9094-6395 -39-Docket No.: 183B-412969-WOY5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp, Aad, or Glu and R7is Lys, Dab, or Orn, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu; provided that: when Y1is dVal, then Y2is dPro.

[0141] 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- Y3- Y4-Y5( I ) , wherein:R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Orn, Dab, Aad, Asp, and Glu;Y1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;Y3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;SMRH:4906-9094-6395 -40-Docket No.: 183B-412969-WOY5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp, Aad, or Glu and R7is Lys, Dab, or Orn, or R2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 2);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 3);Ac-Nle-c[Glu-His-dPhe-Arg-Trp-Orn]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 4);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 5);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Nle-c[Orn-His-dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 8);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 9);Ac-Nle-c[Dab-His-dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 10);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 11 );Ac-Nle-c[Aad-His-dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 12); andAc-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 13), wherein c represents cyclization through a lactam bond between R2and R7.

[0142] In some embodiments of the sequence of Formula (I), the melanocortin analog is cyclized through a lactam bond between Glu at R2and Orn at R7. In further embodiments, R4is p(F)dPhe. Accordingly, in some embodiments, the sequence of Formula (I) is a sequence of Formula (IA):R1- R2- R3- R4- R5- R6- R7- Y1- Y2-Y3-Y4- Y5( I A) , wherein:SMRH:4906-9094-6395 -41 -Docket No.: 183B-412969-WOR1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is Orn;Y1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;Y3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp, Aad, or Glu and R7is Lys, Dab, or Orn, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu; provided that: when Y1is dVal, then Y2is dPro.

[0143] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA):R1- R2- R3- R4- R5- R6- R7- Y1- Y2-Y3-Y4- Y5( I A) , wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);SMRH:4906-9094-6395 -42-Docket No.: 183B-412969-WOR3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is Orn;Y1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;Y3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7, provided that: when Y1is dVal, then Y2is dPro.

[0144] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA), wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is Orn;SMRH:4906-9094-6395 -43-Docket No.: 183B-412969-WOY1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;Y3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 5), wherein c represents cyclization through a lactam bond between R2and R7.

[0145] In some embodiments of the sequence of Formula (I) or (IA), Y1is dVal, Y2is dPro, and the C-terminus of the melanocortin analog is extended one residue, two residues, or three residues beyond dPro. Accordingly, in some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (I A(i)) :R1- R2- R3- R4- R5- R6- R7-Y1-Y2-Y3-Y4-Y5( I A(i ) ) , wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is D-valine (dVal);SMRH:4906-9094-6395 -44-Docket No.: 183B-412969-WOY2is D-proline (dPro);Y3is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), Asp, oc-phenylglycine (Phg), D-oc-phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y4is absent or is selected from the group consisting of dSer, dPhe, Phg, dPhg, Asp, Orn, dOrn, dAsp, dNIe, dAla, and Gly;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0146] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(i)):R1- R2- R3- R4- R5- R6- R7- Y1- Y2- Y3- Y4-Y5( I A ( i ) ) , wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is D-valine (dVal);Y2is D-proline (dPro);Y3is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), Asp, oc-phenylglycine (Phg), D-oc-phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y4is absent or is selected from the group consisting of dSer, dPhe, Phg, dPhg, Asp, Orn, dOrn, dAsp, dNIe, dAla, and Gly;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe; andSMRH:4906-9094-6395 -45-Docket No.: 183B-412969-WO the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0147] In some embodiments, when the C-terminus comprises one, two, or three residues extended beyond Y2, then the C-terminal amino acid is selected from dSer, dPhe, dOrn, dAsp, and dNIe. The C-terminal amino acid may immediately follow the dVal-dPro moiety in the case of a one residue extension or may be separated from the dVal-dPro moiety by one or two residues in the case of a two or three residue extension. In some embodiments, the C-terminal amino acid is separated from the dVal-dPro moiety by one or two spacer amino acids. The spacer amino acids may each independently be an aliphatic amino acid. In other embodiments, the C-terminal amino acid is separated from the dVal- dPro moiety by one or two additional extension amino acids selected from dSer, dPhe, dOrn, dAsp, and dNIe. In still other embodiments, the C-terminal amino acid is separated from the dVal-dPro moiety by one spacer amino acid and one additional extension amino acid.

[0148] Accordingly, in some embodiments of the sequence of any one of Formulae (I)- (IA(i)):R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is D-valine (dVal);Y2is D-proline (dPro);Y3is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), D-alanine (dAla), and glycine (Gly);Y4is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, dAla, and Gly;SMRH:4906-9094-6395 -46-Docket No.: 183B-412969-WOY5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0149] In some embodiments, when the C-terminus comprises one or two three residues extended beyond Y2, then the C-terminal amino acid is selected from Phg, dPhg, Asp, and Orn. The C-terminal amino acid may immediately follow the dVal-dPro moiety in the case of a one residue extension or may be separated from the dVal-dPro moiety by one residue in the case of a two residue extension. In some embodiments, the C-terminal amino acid is separated from the dVal-dPro moiety by one spacer amino acid. The spacer amino acid may be an aliphatic amino acid.

[0150] Accordingly, in some embodiments of the sequence of any one of Formulae (I)- (IA(i)):R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is D-valine (dVal);Y2is D-proline (dPro);Y3is selected from the group consisting of Asp, oc-phenylglycine (Phg), D-oc- phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y4is absent or is selected from the group consisting of Phg, dPhg, Asp, and Orn;Y5is absent; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0151] In some embodiments of the sequence of Formula (I) or (IA), the C-terminus of the melanocortin analog terminates with a dVal-dPro moiety and is extended by insertion ofSMRH:4906-9094-6395 -47-Docket No.: 183B-412969-WO one residue, two residues, or three residues between the last cyclization residue and the terminal dVal-dPro moiety. Accordingly, in some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (IA(ii)):R1- R2- R3- R4- R5- R6- R7- Y1- Y2- Y3-Y4- Y5( I A ( i i ) ) , wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), Asp, oc-phenylglycine (Phg), D-oc-phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-valine (dVal), dSer, dPhe, dOrn, dAsp, dNIe, Asp, Phg, dPhg, Orn, dAla, and Gly;Y3is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, dOrn, dAsp, dNIe, Asp, Phg, dPhg, and Orn;Y4is absent, dPro, or dVal;Y5is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0152] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(ii)) :R1- R2- R3- R4- R5- R6- R7- Y1- Y2- Y3-Y4- Y5( I A(i i ) ) , wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);SMRH:4906-9094-6395 -48-Docket No.: 183B-412969-WOR3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), Asp, oc-phenylglycine (Phg), D-oc-phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-valine (dVal), dSer, dPhe, dOrn, dAsp, dNIe, Asp, Phg, dPhg, Orn, dAla, and Gly;Y3is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, dOrn, dAsp, dNIe, Asp, Phg, dPhg, and Orn;Y4is absent, dPro, or dVal;Y5is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0153] In some embodiments, when the C-terminus comprises one, two, or three residues inserted between the final cyclization residue and the terminal dVal-dPro moiety, the dVal-dPro moiety is immediately preceded by an extension amino acid selected from dSer, dPhe, dOrn, dAsp, and dNIe. In the case of a two or three residue extension, one or two spacer amino acids may be inserted between the final cyclization residue and the extension amino acid immediately preceding the C-terminal dVal-dPro moiety. The spacer amino acids may each independently be an aliphatic amino acid. Alternatively, one or two additional extension amino acids or one additional extension amino acid and one spacer amino acid may be inserted between the final cyclization residue and the final extension amino acid.

[0154] Accordingly, in some embodiments of the sequence of any one of Formula (I), (IA), and (IA(ii)):R1is norleucine (Nle);R2is glutamic acid (Glu);SMRH:4906-9094-6395 -49-Docket No.: 183B-412969-WOR3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-valine (dVal), dSer, dPhe, dOrn, dAsp, dNIe, dAla, and Gly;Y3is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, dOrn, dAsp, and dNIe;Y4is absent, dPro, or dVal;Y5is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0155] In some embodiments, when the C-terminus comprises one, two, or three residues inserted between the final cyclization residue and the terminal dVal-dPro moiety, the dVal-dPro moiety is immediately preceded by an extension amino acid selected from Phg, dPhg, Asp, and Orn. In the case of a two or three residue extension, one or two spacer amino acids may be inserted between the final cyclization residue and the extension amino acid immediately preceding the C-terminal dVal-dPro moiety. The spacer amino acids may each independently be an aliphatic amino acid.

[0156] Accordingly, in some embodiments of the sequence of any one of Formula (I), (IA), and (IA(ii)):R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);SMRH:4906-9094-6395 -50-Docket No.: 183B-412969-WOR6is tryptophan (Trp);R7is ornithine (Orn);Y1is selected from the group consisting of Asp, oc-phenylglycine (Phg), D-oc- phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-valine (dVal), Asp, Phg, dPhg, Orn, dAla, and Gly;Y3is selected from the group consisting of D-proline (dPro), dVal, Asp, Phg, dPhg, and Orn;Y4is absent, dPro, or dVal;Y5is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0157] In some embodiments of the sequence of Formula (I), the non-naturally occurring melanocortin analog is cyclized through a lactam bond between an amino acid other than Glu at R2and an amino acid other than Orn at R7. Accordingly, in some embodiments, the sequence of Formula (I) is a sequence of Formula (IB):R1- R2- R3- R4- R5- R6- R7-Y1-Y2-Y3-Y4-Y5(IB), wherein:R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Dab, Aad, Asp, and glutamic acid (Glu);Y1is selected from the group consisting of D-valine (dVal), D-ornithine (dOrn), D- alanine (dAla), and glycine (Gly);SMRH:4906-9094-6395 -51 -Docket No.: 183B-412969-WOY2is selected from the group consisting of D-proline (dPro), dVal, dOrn, dAla, and Gly;Y3is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y4is absent or is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y5is absent, dOrn, or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp or Aad and R7is Lys or Dab, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu, provided that: when Y1is dVal, then Y2is dPro.

[0158] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB):R1- R2- R3- R4- R5- R6- R7-Y1-Y2-Y3-Y4-Y5(IB), wherein:R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Dab, Aad, Asp, and glutamic acid (Glu);Y1is selected from the group consisting of D-valine (dVal), D-ornithine (dOrn), D- alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dOrn, dAla, and Gly;Y3is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;SMRH:4906-9094-6395 -52-Docket No.: 183B-412969-WOY4is absent or is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y5is absent, dOrn, or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp or Aad and R7is Lys or Dab, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu, provided that: when Y1is dVal, then Y2is dPro.

[0159] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB), wherein:R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Dab, Aad, Asp, and glutamic acid (Glu);Y1is selected from the group consisting of D-valine (dVal), D-ornithine (dOrn), D- alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dOrn, dAla, and Gly;Y3is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y4is absent or is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y5is absent, dOrn, or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp or Aad and R7is Lys or Dab, orSMRH:4906-9094-6395 -53-Docket No.: 183B-412969-WOR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 2);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 3);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Nle-c[Orn-His-dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 8);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 9);Ac-Nle-c[Dab-His-dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 10);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 11 );Ac-Nle-c[Aad-His-dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 12); andAc-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 13), wherein c represents cyclization through a lactam bond between R2and R7.

[0160] In some embodiments, the non-naturally occurring melanocortin analog has one or more beta hairpin (p-hairpin) and / or beta turn (p-turn) structures. In some embodiments, R3of the sequence according to Formula (I) provides the p-hairpin and / or p-turn structures of the melanocortin analog.

[0161] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog is modified. The N-terminus of the melanocortin analog may be modified by any functional group known in the art, such as, for example, an acyl group, an imine group, an amide group, a urea group, a carbamate group, a sulfonamide group, and an alkylamine group.

[0162] As will be appreciated by the skilled artisan, non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (l)-(IB(ii)), 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-SMRH:4906-9094-6395 -54-Docket No.: 183B-412969-WO terminus at the right most residue. Accordingly, the N-terminus of a non-naturally melanocortin analog comprising a sequence of any one of Formulae (l)-(IB(ii)) may be at X1. Similarly, the C-terminus of a non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (l)-(IB(ii)) may be at Y2.

[0163] 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

[0164] Alternatively, in some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is not modified.

[0165] The moiety Y1Y2Y3Y4Y5represents a C-terminus of the non-naturally occurring melanocortin analog. In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog terminates with a dVal-dPro moiety. In other embodiments the C- terminus of the non-naturally occurring melanocortin analog initiates with a dVal-dPro moiety. The dVal-dPro moiety may confer improved properties on the melanocortin analog, such as increased plasma duration and improved transport across the blood-brain-barrier, the epithelium, and / or gastrointestinal tract, or increased stability against biodegradation.

[0166] In some embodiments, Y1-Y3are present and Y4and Y5are absent. In some embodiments, Y1is dVal, Y2is dPro, and Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, Phg, dPhg, Asp, and Orn. In other embodiments, Y1is dVal, Y2is dPro, and Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In still other embodiments, Y1is dVal, Y2is dPro, and Y3is selected from the group consisting of Phg, dPhg, Asp, and Orn.

[0167] In some embodiments, Y1is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, Phg, dPhg, Asp, and Orn, Y2is dVal, and Y3is dPro. In other embodiments, Y1is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe, Y2is dVal, and Y3is dPro. In still other embodiments, Y1is selected from the group consisting of Phg, dPhg, Asp, and Orn, Y2is dVal, and Y3is dPro.SMRH:4906-9094-6395 -55-Docket No.: 183B-412969-WO

[0168] In some embodiments, Y1-Y4are present and Y5is absent. In some embodiments, Y1is dVal, Y2is dPro, Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, dAla, and Gly, and Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, Phg, dPhg, Asp, and Orn. In some embodiments, Y1is dVal, Y2is dPro, Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, dAla, and Gly, and Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, Y1is dVal, Y2is dPro, and Y3and Y4are each independently selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, Y1is dVal, Y2is dPro, Y3is dAla or Gly, and Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, Y1is dVal, Y2is dPro, Y3is dAla or Gly, and Y4is selected from the group consisting of Phg, dPhg, Asp, and Orn.

[0169] In some embodiments, Y1is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, dAla, and Gly, Y2is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, Phg, dPhg, Asp, and Orn, Y3is dVal, and Y4is dPro. In some embodiments, Y1is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, dAla, and Gly, Y2is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe, Y3is dVal, and Y4is dPro. In some embodiments, Y1and Y2are each independently selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe, Y3is dVal, and Y4is dPro. In some embodiments, Y1is dAla or Gly, Y2is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe, Y3is dVal, and Y4is dPro. In some embodiments, Y1is dAla or Gly, Y2is selected from the group consisting of Phg, dPhg, Asp, and Orn, Y3is dVal, and Y4is dPro.

[0170] In some embodiments, Y1-Y5are present. In some embodiments, Y1is dVal, Y2is dPro, Y3is dAla or Gly, Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, dAla, and Gly, and Y5is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, Y1is dVal, Y2is dPro, Y3and Y4are each independently dAla or Gly, and Y5is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, Y1is dVal, Y2is dPro, Y3is dAla or Gly, and Y4and Y5are each independently is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.SMRH:4906-9094-6395 -56-Docket No.: 183B-412969-WO

[0171] In some embodiments, Y1is dAla or Gly, Y2is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, dAla, and Gly, Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, Phg, dPhg, Asp, and Orn, Y4is dVal, and Y5is dPro. In some embodiments, Y1is dAla or Gly, Y2and Y3are each independently selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, Y4is dVal, and Y5is dPro. In some embodiments, Y1and Y2are each independently dAla or Gly, Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, Phg, dPhg, Asp, and Orn, Y4is dVal, and Y5is dPro. In some embodiments, Y1and Y2are each independently dAla or Gly, Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe, Y4is dVal, and Y5is dPro. In some embodiments, Y1and Y2are each independently dAla or Gly, Y3is selected from the group consisting of Phg, dPhg, Asp, and Orn, Y4is dVal, and Y5is dPro.

[0172] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified. The C-terminus of the melanocortin analog may be modified by any functional group known in the art, such as, for example, an amide group, an ester group, and an aldehyde group.

[0173] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an amide groupthe sequence of Formula (I), a non-naturally occurring melanocortin analog with a C-terminus modified by an amide may be represented by a terminal -NH2.

[0174] In some embodiments of any one of Formulae (l)-(IB), the C-terminus of the non-naturally occurring melanocortin analog is not modified. In the sequence of any one of Formulae (l)-(IB), a non-naturally occurring melanocortin analog with an unmodified C- terminus may be represented by -OH or by the absence of a C-terminal group.

[0175] In some embodiments of any one of Formulae (l)-(IB), the non-naturally occurring melanocortin analog disclosed herein is cyclized. For example, the non-naturally occurring melanocortin analog may be cyclized through a moiety selected from the group consisting of: a side-chain lactam bridge between R2and R7when R2is Glu, Asp, or Aad,SMRH:4906-9094-6395 -57-Docket No.: 183B-412969-WO and R7is Lys, Orn, or Dab, and a side-chain lactam bridge between R2and R7when R2is Lys, Orn, or Dab, and R7is Asp, Glu, or Aad.

[0176] In some embodiments, the melanocortin analog is cyclized through a side-chain lactam bridge between a carboxylic acid-containing amino acid at R2and an amine- containing amino acid at R7. In some embodiments, the melanocortin analog is cyclized through a lactam bond between Glu at R2and Orn at R7. In further embodiments, R3is His.

[0177] Non-naturally occurring melanocortin analogs of the present technology have an extended C-terminus. Melanocortin analogs with an extended C-terminus may have three or more, four or more, or five exocyclic residues at the C-terminus. In some embodiments, the melanocortin analog has an extended C-terminus in which the first two exocyclic residues, namely, Y1and Y2, are dVal-dPro.

[0178] In some embodiments, Y1and Y2form the moiety dVal-dPro, Y3is present, and Y4and Y5are absent. In some embodiments, when Y1and Y2form the moiety dVal-dPro, and Y4and Y5are absent, Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-NH2(SEQ ID NO: 14); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-NH2(SEQ ID NO: 15); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-NH2(SEQ ID NO: 16); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-NH2(SEQ ID NO: 17); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-NH2(SEQ ID NO: 18), wherein c represents cyclization through R2and R7via a lactam bond.

[0179] In other embodiments, when Y1and Y2form the moiety dVal-dPro, and Y4and Y5are absent, Y3is selected from the group consisting of Phg, dPhg, Asp, and Orn. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Phg-NH2(SEQ ID NO: 19); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhg-NH2(SEQ ID NO: 20); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Asp-NH2(SEQ ID NO: 21 ); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Orn-NH2(SEQ ID NO: 22),SMRH:4906-9094-6395 -58-Docket No.: 183B-412969-WO wherein c represents cyclization through R2and R7via a lactam bond.

[0180] In some embodiments, Y1and Y2form the moiety dVal-dPro, Y3and Y4are present, and Y5is absent. In some embodiments, Y3is a spacer amino acid. Spacer amino acids may be used to confer length to the C-terminus of the melanocortin analogs without effecting binding activity or potency at the melanocortin 3 and / or 4 receptors. For example, while spacer amino acids may not bind to the melanocortin 3 or melanocortin 4 receptor, spacer amino acids may allow other amino acids present in the melanocortin analog to bind to a portion of the melanocortin 3 and / or melanocortin 4 receptor and / or interact with the melanocortin 3 and / or melanocortin 4 receptor more favorably. Such length may further improve the stability and / or bioavailability of the melanocortin analogs. Suitable spacer amino acids include dAla and Gly. As such, in some embodiments, Y3is dAla or Gly.

[0181] In some embodiments, when Y1and Y2form the moiety dVal-dPro and Y5is absent, then Y3is dAla or Gly. In further embodiments, Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-NH2(SEQ ID NO: 23); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-NH2(SEQ ID NO: 24); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 25); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-NH2(SEQ ID NO: 26); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-NH2(SEQ ID NO: 27); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dSer-NH2(SEQ ID NO: 28);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dPhe-NH2(SEQ ID NO: 29); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 30); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dAsp-NH2(SEQ ID NO: 31 ); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dNle-NH2(SEQ ID NO: 32), wherein c represents cyclization through R2and R7via a lactam bond.

[0182] Alternatively, in some embodiments, when Y1and Y2form the moiety dVal-dPro, Y3is dAla or Gly, and Y5is absent, then Y4is selected from the group consisting of Phg, dPhg, Asp, and Orn. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:SMRH:4906-9094-6395 -59-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-Phg-NH2(SEQ ID NO: 33); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhg-NH2(SEQ ID NO: 34); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-Asp-NH2(SEQ ID NO: 35); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-Orn-NH2(SEQ ID NO: 36); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Phg-NH2(SEQ ID NO: 37); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dPhg-NH2(SEQ ID NO: 38); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Asp-NH2(SEQ ID NO: 39); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Orn-NH2(SEQ ID NO: 40), wherein c represents cyclization through R2and R7via a lactam bond.

[0183] In some embodiments, when Y1and Y2form the moiety dVal-dPro and Y5is absent, then Y3and Y4are each independently selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, Y3and Y4are the same amino acid. In other embodiments, Y3and Y4are different amino acids. For example, when Y3and Y4are each independently selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe, then Y3may be dSer and Y4may be dSer, or Y3may be dSer and Y4may be dPhe, and so on.

[0184] In some embodiments, when Y1and Y2form the moiety dVal-dPro and Y5is absent, then Y3is dSer and Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In other embodiments, Y3is dPhe and Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In other embodiments, Y3is dOrn and Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In still other embodiments, Y3is dAsp and Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In yet other embodiments, Y3is dNIe and Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dSer-NH2(SEQ ID NO: 41 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dPhe-NH2(SEQ ID NO: 42); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dOrn-NH2(SEQ ID NO: 43); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dAsp-NH2(SEQ ID NO: 44); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dNle-NH2(SEQ ID NO: 45);SMRH:4906-9094-6395 -60-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dSer-NH2 (SEQ ID NO: 46); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dPhe-NH2(SEQ ID NO: 47); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dOrn-NH2 (SEQ ID NO: 48); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dAsp-NH2 (SEQ ID NO: 49); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dNle-NH2 (SEQ ID NO: 50); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dSer-NH2 (SEQ ID NO: 51 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dPhe-NH2 (SEQ ID NO: 52); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dOrn-NH2 (SEQ ID NO: 53); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dAsp-NH2 (SEQ ID NO: 54); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dNle-NH2 (SEQ ID NO: 55); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dSer-NH2 (SEQ ID NO: 56); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dPhe-NH2 (SEQ ID NO: 57); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dOrn-NH2 (SEQ ID NO: 58); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dAsp-NH2 (SEQ ID NO: 59); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dNle-NH2 (SEQ ID NO: 60); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dSer-NH2 (SEQ ID NO: 61 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dPhe-NH2 (SEQ ID NO: 62); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dOrn-NH2 (SEQ ID NO: 63); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dAsp-NH2 (SEQ ID NO: 64); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dNle-NH2 (SEQ ID NO: 65), wherein c represents cyclization through R2and R7via a lactam bond.

[0185] In some embodiments, Y1and Y2form the moiety dVal-dPro, Y3-Y5are present. When Y3-Y5are present, the C-terminus may comprise one or two spacer amino acids between the dVal-dPro moiety and the C-terminal amino acid, Y5. For example, in some embodiments, when Y1and Y2form the moiety dVal-dPro and Y3-Y5are present, Y3is a spacer amino acid selected from dAla and Gly. In some embodiments, when Y1and Y2form the moiety dVal-dPro and Y3-Y5are present, Y3and Y4are each spacer amino acids independently selected from dAla and Gly. In some embodiments, all spacer amino acids present in the C-terminus are the same, e.g., all spacer amino acids are dAla or all spacer amino acids are Gly. In other embodiments, the spacer amino acids present in the C- terminus are different.SMRH:4906-9094-6395 -61 -Docket No.: 183B-412969-WO

[0186] In some embodiments, when Y1and Y2form the moiety dVal-dPro and Y3-Y5are present, then Y5is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In further embodiments, Y3and Y4are each independently dAla or Gly. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dSer-NH2(SEQ ID NO: 66); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dPhe-NH2(SEQ ID NO: 67); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 68); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dAsp-NH2(SEQ ID NO: 69); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dNle-NH2(SEQ ID NO: 70); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dSer-NH2(SEQ ID NO: 71 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dPhe-NH2(SEQ ID NO: 72); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 73);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dAsp-NH2(SEQ ID NO: 74); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dNle-NH2(SEQ ID NO: 75), wherein c represents cyclization through R2and R7via a lactam bond.

[0187] In some embodiments, when Y1and Y2form the moiety dVal-dPro and Y3-Y5are present, then Y4and Y5are each independently selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In further embodiments, Y3is dAla.

[0188] In some embodiments, when Y1and Y2form the moiety dVal-dPro and Y3-Y5are present, then Y3is dAla. In further embodiments, Y4and Y5are each independently selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, Y4and Y5are the same amino acid. In other embodiments, Y4and Y5are different amino acids. For example, when Y4and Y5are each independently selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe, then Y4may be dSer and Y5may be dSer, or Y4may be dSer and Y5may be dPhe, and so on.

[0189] In some embodiments, when Y1and Y2form the moiety dVal-dPro and Y3is dAla, then Y4is dSer and Y5is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In other embodiments, Y4is dPhe and Y5is selected from the groupSMRH:4906-9094-6395 -62-Docket No.: 183B-412969-WO consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In other embodiments, Y4is dOrn and Y5is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In still other embodiments, Y4is dAsp and Y5is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In yet other embodiments, Y4is dNIe and Y5is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dSer-NH2(SEQ ID NO: 76); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dPhe-NH2(SEQ ID NO: 77); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dOrn-NH2(SEQ ID NO: 78); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dAsp-NH2(SEQ ID NO: 79); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dNle-NH2(SEQ ID NO: 80); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dSer-NH2(SEQ ID NO: 81 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dPhe-NH2(SEQ ID NO:82);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dOrn-NH2(SEQ ID NO:83);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dAsp-NH2(SEQ ID NO:84);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dNle-NH2(SEQ ID NO: 85); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dSer-NH2(SEQ ID NO: 86); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dPhe-NH2(SEQ ID NO: 87);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dOrn-NH2(SEQ ID NO: 88); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dAsp-NH2(SEQ ID NO:184);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dNle-NH2(SEQ ID NO:185);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dSer-NH2(SEQ ID NO:186);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dPhe-NH2(SEQ ID NO:187);SMRH:4906-9094-6395 -63-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dOrn-NH2(SEQ ID NO:188);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dAsp-NH2(SEQ ID NO:189);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dNle-NH2(SEQ ID NO:190);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dSer-NH2(SEQ ID NO:191 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dPhe-NH2(SEQ ID NO:192);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dOrn-NH2(SEQ ID NO:193);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dAsp-NH2(SEQ ID NO:194); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dNle-NH2(SEQ ID NO:195), wherein c represents cyclization through R2and R7via a lactam bond.

[0190] In some embodiments, the melanocortin analog has an extended C-terminus in which the last two exocyclic residues for a dVal-dPro moiety. Accordingly, the C-terminus may comprise one, two, or three amino acids between the last cyclization residue and the dVal-dPro moiety. In some embodiments, the amino acid immediately preceding the dVal- dPro moiety is selected from dSer, dPhe, dOrn, dAsp, dNIe, Phg, dPhg, Asp, and Orn. In some embodiments, the amino acid immediately preceding the dVal-dPro moiety is selected from dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, the amino acid immediately preceding the dVal-dPro moiety is selected from Phg, dPhg, Asp, and Orn.

[0191] In some embodiments, Y2and Y3form the dVal-dPro moiety and Y4and Y5are absent. In further embodiments, Y1is selected from dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dVal-dPro-NH2(SEQ ID NO: 89);SMRH:4906-9094-6395 -64-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dVal-dPro-NH2(SEQ ID NO: 90); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dVal-dPro-NH2(SEQ ID NO: 91 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dVal-dPro-NH2(SEQ ID NO: 92); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dVal-dPro-NH2(SEQ ID NO: 93), wherein c represents cyclization through R2and R7via a lactam bond.

[0192] Alternatively, in some embodiments, when Y2and Y3form the dVal-dPro moiety and Y4and Y5are absent, then Y1is selected from Phg, dPhg, Asp, and Orn. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Phg-dVal-dPro-NH2(SEQ ID NO: 94); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhg-dVal-dPro-NH2(SEQ ID NO: 95); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Asp-dVal-dPro-NH2; (SEQ ID NO: 96) and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Orn-dVal-dPro-NH2(SEQ ID NO: 97), wherein c represents cyclization through R2and R7via a lactam bond.

[0193] In some embodiments, Y3and Y4form the dVal-dPro moiety and Y5is absent. In some embodiments, when Y3and Y4form the dVal-dPro moiety and Y5is absent, then Y2is selected from dSer, dPhe, dOrn, dAsp, and dNIe. In further embodiments, Y1is dAla or Gly. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dVal-dPro-NH2(SEQ ID NO: 98); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dVal-dPro-NH2(SEQ ID NO: 99); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 100); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 101 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dVal-dPro-NH2(SEQ ID NO: 102); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dSer-dVal-dPro-NH2(SEQ ID NO: 103); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dPhe-dVal-dPro-NH2(SEQ ID NO: 104); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 105); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 106); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dNle-dVal-dPro-NH2(SEQ ID NO: 107), wherein c represents cyclization through R2and R7via a lactam bond.SMRH:4906-9094-6395 -65-Docket No.: 183B-412969-WO

[0194] Alternatively, in some embodiments, when Y3and Y4form the moiety dVal-dPro, Y5is absent, and Y1is dAla or Gly, then Y2is selected from the group consisting of Phg, dPhg, Asp, and Orn. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-Phg-dVal-dPro-NH2(SEQ ID NO: 108); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhg-dVal-dPro-NH2(SEQ ID NO: 109); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Phg-dVal-dPro-NH2(SEQ ID NO: 1 10); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dPhg-dVal-dPro-NH2(SEQ ID NO: 111 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-Asp-dVal-dPro-NH2(SEQ ID NO: 112);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Asp-dVal-dPro-NH2(SEQ ID NO: 1 13);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-Orn-dVal-dPro-NH2(SEQ ID NO: 114); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Orn-dVal-dPro-NH2(SEQ ID NO: 115), wherein c represents cyclization through R2and R7via a lactam bond.

[0195] In some embodiments, when Y3and Y4form the dVal-dPro moiety and Y5is absent, then Y1and Y2are each independently selected from dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, Y1and Y2are the same amino acid. In other embodiments, Y1and Y2are different amino acids. For example, when Y1and Y2are each independently selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe, then Y1may be dSer and Y2may be dSer, or Y1may be dSer and Y2may be dPhe, and so on.

[0196] In some embodiments, when Y3and Y4form the moiety dVal-dPro and Y5is absent, then Y1is dSer and Y2is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In other embodiments, Y1is dPhe and Y2is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In other embodiments, Y1is dOrn and Y2is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In still other embodiments, Y1is dAsp and Y2is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In yet other embodiments, Y1is dNIe and Y2is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dSer-dVal-dPro-NH2(SEQ ID NO: 116); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dPhe-dVal-dPro-NH2(SEQ ID NO: 1 17);SMRH:4906-9094-6395 -66-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dOrn-dVal-dPro-NH2(SEQ ID NO: 118); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dAsp-dVal-dPro-NH2(SEQ ID NO: 1 19); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dNle-dVal-dPro-NH2(SEQ ID NO: 120); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dSer-dVal-dPro-NH2(SEQ ID NO: 121 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dPhe-dVal-dPro-NH2(SEQ ID NO: 122); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dOrn-dVal-dPro-NH2(SEQ ID NO: 123); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dAsp-dVal-dPro-NH2(SEQ ID NO: 124); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dNle-dVal-dPro-NH2(SEQ ID NO: 125);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dSer-dVal-dPro-NH2(SEQ ID NO: 126); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dPhe-dVal-dPro-NH2(SEQ ID NO: 127); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dOrn-dVal-dPro-NH2(SEQ ID NO: 128); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dAsp-dVal-dPro-NH2(SEQ ID NO: 129);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dNle-dVal-dPro-NH2(SEQ ID NO: 130); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dSer-dVal-dPro-NH2(SEQ ID NO: 131 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dPhe-dVal-dPro-NH2(SEQ ID NO: 132); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dOrn-dVal-dPro-NH2(SEQ ID NO: 133);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dAsp-dVal-dPro-NH2(SEQ ID NO: 134); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dNle-dVal-dPro-NH2(SEQ ID NO: 135); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dSer-dVal-dPro-NH2(SEQ ID NO: 136); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dPhe-dVal-dPro-NH2(SEQ ID NO: 137);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dOrn-dVal-dPro-NH2(SEQ ID NO: 138);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dAsp-dVal-dPro-NH2(SEQ ID NO: 139); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dNle-dVal-dPro-NH2(SEQ ID NO: 140), wherein c represents cyclization through R2and R7via a lactam bond.

[0197] In some embodiments, Y4and Y5form the dVal-dPro moiety. In further embodiments, Y1is dAla or Gly.

[0198] In some embodiments, Y4and Y5form the dVal-dPro moiety and Y1and Y2are each independently dAla or Gly. In some embodiments, Y1and Y2are the same, e.g., Y1and Y2are both dAla or Y1and Y2are both Gly. In other embodiments, Y1and Y2are different, e.g., Y1is dAla and Y2is Gly or Y1is Gly and Y2is dAla. In some embodiments,SMRH:4906-9094-6395 -67-Docket No.: 183B-412969-WO when Y4and Y5form the dVal-dPro moiety and Y1and Y2are each independently dAla or Gly, then Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dSer-dVal-dPro-NH2(SEQ ID NO:141 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dPhe-dVal-dPro-NH2(SEQ ID NO:142);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO:143);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO:144);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dNle-dVal-dPro-NH2(SEQ ID NO:145);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dSer-dVal-dPro-NH2(SEQ ID NO: 146); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dPhe-dVal-dPro-NH2(SEQ ID NO: 147); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 148); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 149); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dNle-dVal-dPro-NH2(SEQ ID NO: 150), wherein c represents cyclization through R2and R7via a lactam bond.

[0199] Alternatively, in some embodiments, when Y4and Y5form the dVal-dPro moiety and Y1and Y2are each independently dAla or Gly, then Y3is selected from the group consisting of Phg, dPhg, Asp, and Orn. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-Phg-dVal-dPro-NH2(SEQ ID NO: 151 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dPhg-dVal-dPro-NH2(SEQ ID NO: 152);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-Phg-dVal-dPro-NH2(SEQ ID NO: 153); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dPhg-dVal-dPro-NH2(SEQ ID NO: 154); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-Asp-dVal-dPro-NH2(SEQ ID NO: 155);SMRH:4906-9094-6395 -68-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-Asp-dVal-dPro-NH2 (SEQ ID NO: 156); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-Orn-dVal-dPro-NH2(SEQ ID NO: 157); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-Orn-dVal-dPro-NH2 (SEQ ID NO: 158), wherein c represents cyclization through R2and R7via a lactam bond.

[0200] In some embodiments, Y4and Y5form the moiety dVal-dPro and Y1is dAla. In further embodiments, Y2and Y3are each independently selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, Y2and Y3are the same amino acid. In other embodiments, Y2and Y3are different amino acids. For example, when Y2and Y3are each independently selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe, then Y2may be dSer and Y3may be dSer, or Y2may be dSer and Y3may be dPhe, and so on.

[0201] In some embodiments, when Y4and Y5form the moiety dVal-dPro and Y1is dAla, then Y2is dSer and Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In other embodiments, Y2is dPhe and Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In other embodiments, Y2is dOrn and Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In still other embodiments, Y2is dAsp and Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In yet other embodiments, Y2is dNIe and Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dSer-dVal-dPro-NH2(SEQ ID NO:159);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dPhe-dVal-dPro-NH2(SEQ ID NO:160);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dOrn-dVal-dPro-NH2 (SEQ ID NO:161 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dAsp-dVal-dPro-NH2(SEQ ID NO:162);SMRH:4906-9094-6395 -69-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dNle-dVal-dPro-NH2(SEQ ID NO:163);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dSer-dVal-dPro-NH2(SEQ ID NO:164);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dPhe-dVal-dPro-NH2(SEQ ID NO:165);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dOrn-dVal-dPro-NH2(SEQ ID NO:166);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dAsp-dVal-dPro-NH2(SEQ ID NO:167);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dNle-dVal-dPro-NH2(SEQ ID NO:168);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dSer-dVal-dPro-NH2(SEQ ID NO:169);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dPhe-dVal-dPro-NH2(SEQ ID NO:1 0);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dOrn-dVal-dPro-NH2(SEQ ID NO:171 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dAsp-dVal-dPro-NH2(SEQ ID NO:172);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dNle-dVal-dPro-NH2(SEQ ID NO:173);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dSer-dVal-dPro-NH2(SEQ ID NO:174);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dPhe-dVal-dPro-NH2(SEQ ID NO:175);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dOrn-dVal-dPro-NH2(SEQ ID NO:176);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dAsp-dVal-dPro-NH2(SEQ ID NO:177);SMRH:4906-9094-6395 -70-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dNle-dVal-dPro-NH2(SEQ ID NO:178);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dSer-dVal-dPro-NH2(SEQ ID NO:1 9);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dPhe-dVal-dPro-NH2(SEQ ID NO:180);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dOrn-dVal-dPro-NH2(SEQ ID NO:181 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dAsp-dVal-dPro-NH2(SEQ ID NO:182); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dNle-dVal-dPro-NH2(SEQ ID NO:183), wherein c represents cyclization through R2and R7via a lactam bond.

[0202] In some embodiments, the melanocortin analog is cyclized through a side-chain lactam bridge between a carboxylic acid-containing amino acid other than Glu at R2and an amine-containing amino acid other than Orn at R7.

[0203] In some embodiments, the melanocortin analog is cyclized through a lactam bond between Asp at R2and Lys at R7. In further embodiments R4is p(F)dPhe. In still further embodiments, Y1is dOrn, dAla, Gly, or dVal, Y2and Y3are each independently dVal, dPro, dOrn, dAla, or Gly, Y4is absent, dVal, dPro, dOrn, dAla, or Gly, and Y5is absent, dOrn, or dPro. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dOrn-dVal-dPro-NH2(SEQ ID NO: 200); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 201 ); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 202);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 203);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 204); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-dOrn-NH2(SEQ ID NO: 205);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 206);SMRH:4906-9094-6395 -71 -Docket No.: 183B-412969-WOAc-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-dOrn-NH2 (SEQ ID NO: 207);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 208); andAc-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-Gly-dOm-NH2(SEQ ID NO: 209), wherein c represents cyclization through R2and R7via a lactam bond.

[0204] Alternatively, in some embodiments, the melanocortin analog is cyclized through a lactam bond between Asp at R2and Lys at R7, and R4is dPhe. In further embodiments, Y1is dOrn, dAla, Gly, dVal, or dAsp, Y2and Y3are each independently dVal, dPro, dOrn, dAla, dAsp, or Gly, Y4is absent, dVal, dPro, dOrn, dAsp, or dAla, and Y5is absent or dPro. In some embodiments R4is dPhe. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAsp-dVal-dPro-NH2 (SEQ ID NO: 196); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dOrn-dVal-dPro-NH2(SEQ ID NO: 197); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dAsp-dVal-dPro-NH2 (SEQ ID NO: 198); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dOrn-dVal-dPro-NH2 (SEQ ID NO: 199); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 250); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 251 );Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 252); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 253); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 254); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 255); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dAsp-NH2 (SEQ ID NO: 256);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dOrn-NH2(SEQ ID NO: 257);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dAsp-NH2 (SEQ ID NO: 258); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 259); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-dAsp-NH2 (SEQ ID NO: 260); and Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 261 ); wherein c represents cyclization through R2and R7via a lactam bond.

[0205] In some embodiments, the melanocortin analog is cyclized through a lactam bond between Aad at R2and Dab at R7. In further embodiments, R4is p(F)dPhe. In still further embodiments, Y1is dOrn, dAla, Gly, or dVal, Y2and Y3are each independently dVal,SMRH:4906-9094-6395 -72-Docket No.: 183B-412969-WO dPro, dOrn, dAla, or Gly, Y4is absent, dVal, dPro, dOrn, dAla, or Gly, and Y5is absent, dOrn, or dPro. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of: Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dOrn-dVal-dPro-NH2(SEQ ID NO: 210);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 211 ); Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 212);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 213);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 214); Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-dOrn-NH2(SEQ ID NO: 215);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 216); Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 217);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 218); andAc-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 219), wherein c represents cyclization through R2and R7via a lactam bond.

[0206] In some embodiments, the melanocortin analog is cyclized through a side-chain lactam bridge between an amine-containing amino acid at R2and a carboxylic acidcontaining amino acid at R7.

[0207] In some embodiments, the melanocortin analog is cyclized through a lactam bond between Lys at R2and Asp at R7. In further embodiments, R4is p(F)dPhe. In still further embodiments, Y1is dOrn, dAla, Gly, or dVal, Y2and Y3are each independently dVal, dPro, dOrn, dAla, or Gly, Y4is absent, dVal, dPro, dOrn, dAla, or Gly, and Y5is absent, dOrn, or dPro. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dOrn-dVal-dPro-NH2(SEQ ID NO: 220); Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 221 ); Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 222);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 223);SMRH:4906-9094-6395 -73-Docket No.: 183B-412969-WOAc-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 224); Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-dOrn-NH2(SEQ ID NO: 225); Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 226); Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 227);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 228); andAc-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 229), wherein c represents cyclization through R2and R7via a lactam bond.

[0208] Alternatively, in some embodiments, the melanocortin analog is cyclized through a lactam bond between Lys at R2and Asp at R7and R4is dPhe. In further embodiments, Y1is dAsp, dOrn, dAla, Gly, or dVal, Y2and Y3are each independently dVal, dPro, dAsp, dOrn, dAla, or Gly, Y4is absent, dVal, dPro, dAsp, dOrn, dAla, or Gly, and Y5is absent, dOrn, or dPro. In some embodiments, In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAsp-dVal-dPro-NH2(SEQ ID NO: 262); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dOrn-dVal-dPro-NH2(SEQ ID NO: 263); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 264); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 265); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 266); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 267);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 268); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 269); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 270); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 271 ); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dAsp-NH2(SEQ ID NO: 272);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dOrn-NH2(SEQ ID NO: 273);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dAsp-NH2(SEQ ID NO: 274); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 275); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-dAsp-NH2(SEQ ID NO: 276); and Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 277), wherein c represents cyclization through R2and R7via a lactam bond.SMRH:4906-9094-6395 -74-Docket No.: 183B-412969-WO

[0209] In some embodiments, the melanocortin analog is cyclized through a lactam bond between Orn at R2and Glu at R7. In further embodiments, R4is p(F)dPhe. In still further embodiments, Y1is dOrn, dAla, Gly, or dVal, Y2and Y3are each independently dVal, dPro, dOrn, dAla, or Gly, Y4is absent, dVal, dPro, dOrn, dAla, or Gly, and Y5is absent, dOrn, or dPro. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-dOrn-dVal-dPro-NH2(SEQ ID NO: 230); Ac-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 231 ); Ac-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 232);Ac-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 233);Ac-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 234); Ac-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-dOrn-NH2(SEQ ID NO: 235); Ac-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 236); Ac-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 237);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 238); andAc-Nle-c[Om-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 239), wherein c represents cyclization through R2and R7via a lactam bond.

[0210] In some embodiments, the melanocortin analog is cyclized through a lactam bond between Dab at R2and Aad at R7. In further embodiments, R4is p(F)dPhe. In still further embodiments, Y1is dOrn, dAla, Gly, or dVal, Y2and Y3are each independently dVal, dPro, dOrn, dAla, or Gly, Y4is absent, dVal, dPro, dOrn, dAla, or Gly, and Y5is absent, dOrn, or dPro. In some embodiments, the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dOrn-dVal-dPro-NH2(SEQ ID NO: 240); Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 241 ); Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 242);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 243);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 244);SMRH:4906-9094-6395 -75-Docket No.: 183B-412969-WOAc-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-dOrn-NH2(SEQ ID NO: 245); Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 246); Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 247); Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 248); andAc-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 249), wherein c represents cyclization through R2and R7via a lactam bond.

[0211] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence selected from any one of SEQ ID Nos: 14-277.Non-Naturally Occurring Melanocortin Analog Synthesis

[0212] 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.

[0213] 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.

[0214] 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 numerousSMRH:4906-9094-6395 -76-Docket No.: 183B-412969-WO 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).

[0215] In chemical syntheses of peptides, reactive side chain groups of the various amino acid residues are protected with suitable protecting groups, which prevent a chemical reaction from occurring at that site until the protecting group is removed. Also common is the protection of the alpha amino group of an amino acid residue or fragment while that entity reacts at the carboxyl group, followed by the selective removal of the alpha amino protecting group to allow a subsequent reaction to take place at that site. Specific protecting for solid phase synthesis methods and solution phase synthesis methods groups are known to those having ordinary skill in the art.

[0216] 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.

[0217] 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.

[0218] Solid phase synthesis is commenced from the C-terminal end of the peptide by coupling a protected alpha amino acid to a suitable resin. Such starting material is prepared by attaching an alpha amino-protected amino acid by an ester linkage to a p- benzyloxybenzyl alcohol (Wang) resin or a 2-chlorotrityl chloride resin, by an amide bond between an Fmoc-Linker, such as p-[(R,S)-a-[1 -(9H-fluor-en-9-yl)-methoxyformamido]-2,4- dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) to a benzhydrylamine (BHA) resin, or by other means well known in the art. Fmoc-Linker-BHA resin supports are commercially available and generally used when feasible. The resins are carried through repetitive cyclesSMRH:4906-9094-6395 -77-Docket No.: 183B-412969-WO 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.

[0219] Following removal of the alpha amino protecting group, the subsequent protected amino acids are coupled stepwise in the desired order to obtain an intermediate, protected peptide-resin. The activating reagents used for coupling of the amino acids in the solid phase synthesis of the peptides are well known in the art. After the peptide is synthesized, if desired, the orthogonally protected side chain protecting groups may be removed using methods well known in the art for further derivatization of the peptide.

[0220] 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.

[0221] 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-(1 H-benzotriazol-1 -yl)- 1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1 -yl-oxy- tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1 -yl-oxy- tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2-(7-aza-1 H-benzotriazol-1 - yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1 (2H)-pyridyl)-1 ,1 ,3,3- tetramethyluronium tetrafluoroborate (TPTU) or N,N'-dicyclohexylcarbodiimide / 1 - hydroxybenzotriazole (DCCI / HOBt). Coupling is convention initiated by use of a suitableSMRH:4906-9094-6395 -78-Docket No.: 183B-412969-WO base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N-methylmorpholine (NMM).

[0222] Following cleavage of peptides from the solid phase following their synthesis, the peptide can be purified by any number of methods, such as reverse phase high performance liquid chromatography (RP-HPLC), using a suitable column, such as a C18 column. Other methods of separation or purification, such as methods based on the size or charge of the peptide, can also be employed. Once purified, the peptide can be characterized by any number of methods, such as high performance liquid chromatograph (HPLC), amino acid analysis, mass spectrometry, and the like.Salt Forms of Non-Naturally Occurring Melanocortin Analogs

[0223] 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.

[0224] 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.SMRH:4906-9094-6395 -79-Docket No.: 183B-412969-WOAcid 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

[0225] Pharmaceutical compositions comprising the carriers and / or excipients disclosed in the present technology facilitate delivery of the non-naturally occurring melanocortin analog disclosed herein in any of its embodiments to a subject.

[0226] In some embodiments, the non-naturally occurring melanocortin analog is present in a pharmaceutical composition in a therapeutically effective amount. The therapeutically effective amount may be an amount sufficient to elicit a desired response in the subject, such as, for example, weight loss.

[0227] In some embodiments, the non-naturally occurring melanocortin analog is present in the composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the composition. For example, the non-naturally occurring melanocortin analog is present in the composition in a concentration of 0.1 mg / mL to 500 mg / mL, 0.5 mg / mL to 250 mg / mL, 1 mg / mL to 100 mg / mL, 2.5 mg / mL to 50 mg / mL, or 5 mg / mL to 25 mg / mL, relative to a total volume of the composition. In some embodiments, the non-naturally occurring melanocortin analog is present in the composition in a concentration of 5 mg / mL to 100 mg / mL, or about 50 mg / mL, relative to a total volume of the composition.

[0228] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (l)-(IB) and the non-naturally occurring melanocortin analog is present in the composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the composition. For example, the non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (l)-(IB) is present in the composition in a concentration of 5 mg / mL to 100 mg / mL, 10 mg / mL to 75SMRH:4906-9094-6395 -80-Docket No.: 183B-412969-WO 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 any one of Formulae (l)-(IB) is present in the composition in a concentration of about 50 mg / mL, relative to a total volume of the composition.

[0229] In some embodiments, the pharmaceutical composition comprising the non- naturally occurring melanocortin analog is formulated for intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration. In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally. In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously. In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject orally.

[0230] Pharmaceutical compositions disclosed herein formulated for parenteral administration may be in the form of an aqueous or non-aqueous isotonic sterile injection solution or suspension. The term “parenteral”, as used herein, includes subcutaneous, intravenous, intraperitoneal, intramuscular, and intralesional, or infusion techniques. Pharmaceutical compositions disclosed herein formulated for oral administration may be in the form of tablet, capsule, lozenge, pill, sachet, or any other orally deliverable form know in the art.

[0231] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises the non-naturally occurring melanocortin analog of any one of Formulae (l)-(IB) at a concentration at about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol, or even more, depending on the specific peptide selected, the desired response, the route of administration, the formulation and other factors known to those of skill in the art. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (l)-(IB) .SMRH:4906-9094-6395 -81 -Docket No.: 183B-412969-WO

[0232] In some embodiments, the non-naturally occurring melanocortin analog crosses blood-brain-barrier (BBB) of the subject.

[0233] 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.

[0234] The pharmaceutical composition comprising the carriers and / or excipients disclosed in the present technology facilitate delivery (e.g., parenteral administration, in particular subcutaneous injection) of the non-naturally occurring melanocortin analog disclosed herein in any of its embodiments to a subject. Other purposes of the compositions comprising the carriers and / or excipients are to enhance dispersion, solubility, and stability of the non-naturally occurring melanocortin analog, and to reduce adverse injection site reactions.

[0235] The carriers and / or excipients of the pharmaceutical composition can generally include one or more of the following components: a pH buffered aqueous solution comprising (a) sodium acetate, (b) Tris, and (c) water. In some embodiments, all components are compatible with the non-naturally occurring melanocortin analog (i.e., do not react or cause the non-naturally occurring melanocortin analog to react) and are homogeneously dispersed or dissolved uniformly in the composition.

[0236] In some embodiments, the carrier and / or excipient is isotonic.

[0237] 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.SMRH:4906-9094-6395 -82-Docket No.: 183B-412969-WO

[0238] The carriers and / or excipients of the composition may also include a pH buffered aqueous solution which comprises (a) sodium acetate, (b) Tris, and (c) water.

[0239] 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.

[0240] In some embodiments, the pharmaceutical composition further includes water in an amount of about 1 wt% to about 90 wt%, about 10 wt% to about 75 wt%, or about 25 wt% to about 50 wt%, relative to a total weight of the composition.

[0241] In some embodiments, sodium acetate is present in the pharmaceutical composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL, relative to a total volume of the composition. In some embodiments, sodium acetate is present in the 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.

[0242] In some embodiments, sodium acetate is present in the composition in a molar concentration of 5 mM to 700 mM, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a molar concentration of 5 mM to 700 mM, 10 mM to 600 mM, 20 mM to 500 mM, 30 mM to 400 mM, 40 mM to 300 mM, 50 mM to 200 mM, 60 mM to 100 mM, or 70 mM to 80 mM, relative to a total volume of the composition. In some embodiments, sodium acetate is present in the composition in a molar concentration of about 80 mM to about 100 mM, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a molar concentration of 80 mM, 85 mM, 87 mM, 90 mM, 95 mM, or 100 mM, relative to a total volume of the composition.SMRH:4906-9094-6395 -83-Docket No.: 183B-412969-WO

[0243] The term “Tris” represents tris(hydroxymethyl)aminomethane also known as Tris buffer, Tris base, TRIS, tromethamine, tromethamine buffer, Trizma®, Trisamine, Trometamol, Tromethane, Trisaminol, or THAM. In some embodiments, Tris is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, Tris is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL, relative to a total volume of the composition. In some embodiments, Tris is present in the composition in a concentration of about 6 mg / mL to about 8 mg / mL, relative to a total volume of the composition. For example, Tris is present in the composition in a concentration of 6 mg / mL, 6.5 mg / mL, 7 mg / mL, 7.3 mg / mL, 7.6 mg / mL, or 8 mg / mL, relative to a total volume of the composition.

[0244] In some embodiments, Tris is present in the composition in a molar concentration of 2 mM to 500 mM, relative to a total volume of the composition. For example, Tris is present in the composition in a molar concentration of 2 mM to 500 mM, 5 mM to 400 mM, 10 mM to 300 mM, 20 mM to 200 mM, 30 mM to 150 mM, 40 mM to 100 mM, 50 mM to 80 mM, or 60 mM to 70 mM, relative to a total volume of the composition. In some 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.

[0245] 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.

[0246] In addition to sodium acetate and Tris, the composition may further include other buffering agents. Non-limiting examples of additional buffering agents include saline, phosphate, phosphoric acid, citrate, succinate, gluconate, histidine, acetic acid, ascorbate, tartartic acid, maleic acid, glycine, lactate, lactic acid, ascorbic acid, imidazole, bicarbonate, carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, edetate, malate,SMRH:4906-9094-6395 -84-Docket No.: 183B-412969-WO imidazole, and mixtures thereof. In some embodiments, the composition comprises acetic acid as an additional buffering agent.

[0247] 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.

[0248] 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 .

[0249] 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 .

[0250] The pharmaceutical composition may further comprise a preservative agent. Exemplary preservative agents include, but are not limited to, ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, phenol, m-cresol, benzyl alcohol, alpha-tocopherol, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, benzalkonium chloride, phenoxyethanol, and methyl paraben.

[0251] 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.

[0252] 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.SMRH:4906-9094-6395 -85-Docket No.: 183B-412969-WO

[0253] The active ingredient(s) (e.g., the non-naturally occurring melanocortin analog) may be dissolved or suspended in the aforementioned carrier and / or excipient. Additional aqueous or non-aqueous carriers that may facilitate dissolution of the active ingredient include, but are not limited to, ethanol, benzyl alcohol, DMSO, polyethylene glycol, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, and / or various buffers.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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 to4.5 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, or1 .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.SMRH:4906-9094-6395 -86-Docket No.: 183B-412969-WO

[0258] In some embodiments, the pharmaceutical composition further comprises one or more antioxidants. For example, the pharmaceutical composition may comprise ascorbic acid, cysteine, sodium metabisulfite, propyl gallate, butylated hydroxytoluene, and / or butylated hydroxyanisole.

[0259] In some embodiments, the pharmaceutical composition further comprises a surfactant, such as a sorbitan ester.

[0260] In some embodiments, the pharmaceutical composition further comprises a flavoring or scent, such as an aromatic oil.Use of non-naturally occurring melanocortin analogs

[0261] 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 full agonism of MC3R and full or partial agonism of 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 full agonism of MC3R and full or partial agonism of 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.Subjects

[0262] The non-naturally occurring melanocortin analogs of the present technology may be formulated for delivery to a subject in need thereof. The subject may have or be at risk of developing a metabolic dysfunction. In some embodiments, the metabolic dysfunction is selected from the group consisting of obesity, diabetes mellitus, metabolic syndrome, insulin resistance, non-alcoholic fatty liver disease, polycystic ovarian syndrome, metabolicSMRH:4906-9094-6395 -87-Docket No.: 183B-412969-WO acidosis, hypothyroidism, hyperlipidemia, Cushing Syndrome, and metabolic myopathies. In other embodiments, the subject has another condition which is not metabolic dysfunction, but administration of the weight loss agent provides therapeutic benefit to the non-metabolic dysfunction condition.Dosina and Administration

[0263] 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.

[0264] In some embodiments, the non-naturally occurring melanocortin analog 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 analog 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 analog 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 analog is administered at a dose of about 20 mg / kg to about 75 mg / kg per body weight of the subject once daily.

[0265] In some embodiments, the non-naturally occurring melanocortin analog 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 analog isSMRH:4906-9094-6395 -88-Docket No.: 183B-412969-WO 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.

[0266] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 0.001 mg / kg, about 0.01 mg / kg, about 0.10 mg. kg, about 0.5 mg / kg, about 1 .0 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 50 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 400 mg / kg, about 450 mg / kg, or about 500 mg / kg per body weight of the subject once daily or twice daily.

[0267] 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.

[0268] 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

[0269] 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-GenericSMRH:4906-9094-6395 -89-Docket No.: 183B-412969-WO

[0270] 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.

[0271] The process for synthesizing the non-naturally occurring melanocortin analogs was generally performed by a procedure as follows. Each amino acid in the desired sequence of the non-naturally occurring melanocortin analogs was added one at a time in succession to another amino acid or derivative thereof or by a procedure whereby peptide fragments with the desired amino acid sequence were first synthesized conventionally and then condensed to provide the desired peptide. In most cases, the resulting peptide was then cyclized to yield a cyclic peptide.

[0272] 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 solidphase 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.

[0273] 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 alphaamine 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 betweenSMRH:4906-9094-6395 -90-Docket No.: 183B-412969-WO 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)-a-[1 -(9H-fluor-en-9-yl)-methoxyformamido]-2,4-dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) via an amide linkage.

[0274] The non-naturally occurring melanocortin analog was then synthesized by sequential amino acid addition or combination of peptide fragments. Subsequently, the peptide was cleaved from the solid-phase support and purified by methods known in the art, such as, for example, reverse phase high performance liquid chromatography (RP-HPLC) using a suitable column, such as a C18 column. Additionally, or alternatively, other methods of separation or purification were employed, including, but not limited to, methods based on the size or charge of the peptide. Once purified, the peptide was characterized by methods such as high-performance liquid chromatograph (HPLC), amino acid analysis, mass spectrometry, and the like.Example 2: Peptide Synthesis-Protecting Groups

[0275] 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.

[0276] 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-SMRH:4906-9094-6395 -91 -Docket No.: 183B-412969-WO 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.

[0277] 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

[0278] 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.

[0279] Additionally, the cyclized peptide structures were obtained prior to cleavage from the peptide resin. For cyclization through reactive side chain moieties, the desired side chains were deprotected, and the peptide suspended in a suitable solvent and a cyclic coupling agent added. Suitable solvents, for example DMF, dichloromethane (DCM) or 1 - methyl-2-pyrrolidone (NMP), were used for the cyclization. Suitable cyclic coupling reagents (e.g., 2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HBTU), benzotriazole- 1 -yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1 -yl- oxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2-(7-aza-1 H-benzotriazol- 1 -yl)-1 ,1 , 3, 3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1 (2H)-pyridyl)-1 ,1 ,3,3- tetramethyluronium tetrafluoroborate (TPTU), N,N'-dicyclohexylcarbodiimide / 1 - hydroxybenzotriazole (DCCI / HOBt)) were also used for the cyclization. Coupling wasSMRH:4906-9094-6395 -92-Docket No.: 183B-412969-WO initiated by a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N- methylmorpholine (NMM).Example 4: Biological Data

[0280] The agonist and antagonist activity of exemplary non-naturally occurring melanocortin analogs at the melanocortin receptors (e.g., MC1 R, MC3R, MC4R, and MC5R) were measured via cAMP accumulation assay, according to the following procedure. Experimental design and execution were conducted by Epics Therapeutics S.A. EuroscreenFast (Bruxelles, Belgium).Compound Handing

[0281] Compounds were delivered as powder (1 mg) or 10 mM solutions (100 pl) in 100% DMSO. Powders were solubilized in 100% DMSO at a concentration of 10 mM (master solution) in a solvent volume defined. Serial dilutions were performed from master solution in 100% DMSO to obtain intermediate concentrations 200-, 300- or 400-fold higher than the concentrations to be tested, depending on the assay. Each sample was diluted 100- fold in the assay buffer and dispensed in a test plate. Amounts, solvents, and dilutions were estimated based on standard small-molecule drugs. Cell lines used for functional assays are shown in Table 1 .Table 1. Cell linesCompound Testing

[0282] 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 ProtocolSMRH:4906-9094-6395 -93-Docket No.: 183B-412969-WO

[0283] Cyclic AMP (cAMP) Homogenous Time-Resolved Fluorescence (HTRF) assay for Gs coupled receptor:

[0284] 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 KCI, 1.25 mM MgSO4, 124 mM NaCI, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH2PO4, 1.45 mM CaCI2, 0.5 g / l BSA, supplemented with 1 mM IBMX or 25pM Rolipram).

[0285] Dose response curves were performed in parallel with the reference compounds.

[0286] For agonist test (384well): 5 pl of cells were mixed with 5 pl of the test compound at increasing concentrations and then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated 1 -hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit. Reference agonist NDP-a- MSH (Ser-Tyr-Ser-Nle-Glu-His-dPhe-Arg-Trp-Gly-Lys-Pro-Val (SEQ ID NO: 278)) was also tested as a comparator.

[0287] For antagonist test (384well): 5 pl of cells were mixed in the wells of an assay plate with 5 pl of a mix of the test compound at increasing concentrations for a final concentration corresponding to the historical EC80. The plates were then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated 1 -hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit. Reference antagonist SHU9119 (Ac-Nle-c[Asp-His-D-Nal-Arg-Trp-Lys]-NH2 (SEQ ID NO: 279)) was also tested as a comparator.Quality Control for Compound Testing

[0288] 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.SMRH:4906-9094-6395 -94-Docket No.: 183B-412969-WO

[0289] Reference values thus obtained for the test were compared to historical values obtained from the same receptor and used to validate the experimental session.

[0290] 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.

[0291] 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

[0292] Group A included non-naturally occurring melanocortin analogs A1 to A87, all of which are cyclic peptides comprising the motif His-p(F)dPhe-Arg-Trp (SEQ ID NO: 280). Group A melanocortin analogs also comprise Nle at the N-terminus, are cyclized through Glu at position R2and Orn at position R7, and contain the dVal-dPro moiety as the first two exocyclic residues of the C-terminal. Group A non-naturally occurring melanocortin analogs are provided in Table 2.Table 2. Group A non-naturally occurring melanocortin analogsSMRH:4906-9094-6395 -95-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -96-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -97-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -98-Docket No.: 183B-412969-WO

[0293] Group B included non-naturally occurring melanocortin analogs B1 to B95, all of which are cyclic peptides comprising the motif His-p(F)dPhe-Arg-Trp (SEQ ID NO: 280). Group B melanocortin analogs also comprise Nle at the N-terminus, are cyclized through Glu at position R2and Orn at position R7, and contain the dVal-dPro moiety as the last two exocyclic residues of the C-terminal. Group B non-naturally occurring melanocortin analogs are provided in Table 3.Table 3. Group B non-naturally occurring melanocortin analogsSMRH:4906-9094-6395 -99-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -100-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -101 -Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -102-Docket No.: 183B-412969-WO

[0294] Group C included non-naturally occurring melanocortin analogs C1 to 05, all of which are cyclic peptides comprising the motif His-p(F)dPhe-Arg-Trp (SEQ ID NO: 280). Group C melanocortin analogs also comprise Nle at the N-terminus, are cyclized through Asp at position R2and Lys at position R7, and contain the dVal-dPro moiety as the first two exocyclic residues of the C-terminal. Group C non-naturally occurring melanocortin analogs are provided in Table 4.Table 4. Group C non-naturally occurring melanocortin analogsSMRH:4906-9094-6395 -103-Docket No.: 183B-412969-WO

[0295] Group D included non-naturally occurring melanocortin analogs D1 to D5, all of which are cyclic peptides comprising the motif His-p(F)dPhe-Arg-Trp (SEQ ID NO: 280). Group D melanocortin analogs also comprise Nle at the N-terminus, are cyclized through Asp at position R2and Lys at position R7, and contain the dVal-dPro moiety as the last two exocyclic residues of the C-terminal. Group D non-naturally occurring melanocortin analogs are provided in Table 5.Table 5. Group D non-naturally occurring melanocortin analogs

[0296] Group E included non-naturally occurring melanocortin analogs E1 to E6, all of which are cyclic peptides comprising the motif His-dPhe-Arg-Trp (SEQ ID NO: 281 ). Group E melanocortin analogs also comprise Nle at the N-terminus, are cyclized through Asp at position R2and Lys at position R7, and contain the dVal-dPro moiety as the first two exocyclic residues of the C-terminal. Group A non-naturally occurring melanocortin analogs are provided in Table 6.Table 6. Group E non-naturally occurring melanocortin analogsSMRH:4906-9094-6395 -104-Docket No.: 183B-412969-WO

[0297] Group F included non-naturally occurring melanocortin analogs F1 to F10, all of which are cyclic peptides comprising the motif His-dPhe-Arg-Trp (SEQ ID NO: 281 ). GroupF melanocortin analogs also comprise Nle at the N-terminus, are cyclized through Asp at position R2and Lys at position R7, and contain the dVal-dPro moiety as the last two exocyclic residues of the C-terminal. Group F non-naturally occurring melanocortin analogs are provided in Table 7.Table 7. Group F non-naturally occurring melanocortin analogs

[0298] Group G included non-naturally occurring melanocortin analogs G1 to G20, all of which are cyclic peptides comprising the motif His-p(F)dPhe-Arg-Trp (SEQ ID NO: 280). Group G melanocortin analogs also comprise Nle at the N-terminus, are cyclized through Aad at position R2and Dab at position R7, and contain the dVal-dPro moiety as the first two exocyclic residues of the C-terminal. Group G non-naturally occurring melanocortin analogs are provided in Table 8.Table 8. Group G non-naturally occurring melanocortin analogsSMRH:4906-9094-6395 -105-Docket No.: 183B-412969-WO

[0299] Group H included non-naturally occurring melanocortin analogs H1 to H20, all of which are cyclic peptides comprising the motif His-p(F)dPhe-Arg-Trp (SEQ ID NO: 280). Group H melanocortin analogs also comprise Nle at the N-terminus, are cyclized through Aad at position R2and Dab at position R7, and contain the dVal-dPro moiety as the last two exocyclic residues of the C-terminal. Group H non-naturally occurring melanocortin analogs are provided in Table 9.SMRH:4906-9094-6395 -106-Docket No.: 183B-412969-WOTable 9. Group H non-naturally occurring melanocortin analogs

[0300] Group K included non-naturally occurring melanocortin analogs K1 to K6, all of which are cyclic peptides comprising the motif His-dPhe-Arg-Trp (SEQ ID NO: 281 ). Group K melanocortin analogs also comprise Nle at the N-terminus, are cyclized through Lys atSMRH:4906-9094-6395 -107-Docket No.: 183B-412969-WO position R2and Asp at position R7, and contain the dVal-dPro moiety as the first two exocyclic residues of the C-terminal. Group K non-naturally occurring melanocortin analogs are provided in Table 10.Table 10. Group K non-naturally occurring melanocortin analogs

[0301] Group L included non-naturally occurring melanocortin analogs L1 to 10, all of which are cyclic peptides comprising the motif His-dPhe-Arg-Trp (SEQ ID NO: 281 ). Group L melanocortin analogs also comprise Nle at the N-terminus, are cyclized through Lys at position R2and Asp at position R7, and contain the dVal-dPro moiety as the last two exocyclic residues of the C-terminal. Group L non-naturally occurring melanocortin analogs are provided in Table 11 .Table 11. Group L non-naturally occurring melanocortin analogsSMRH:4906-9094-6395 -108-Docket No.: 183B-412969-WOAgonist activity of melanocortin analogs on melanocortin 1 receptor and melanocortin 5 receptor

[0302] Administration of all the exemplary non-naturally occurring melanocortin analogs activated melanocortin 1 receptor (MC1 R) and melanocortin 5 receptor (MC5R) activity, as measured by cAMP levels (Table 12).Table 12. Dose-response results of melanocortin analogs and control against the melanocortin 1 receptor (MC1 R) and the melanocortin 5 receptor (MC5R)SMRH:4906-9094-6395 -109-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -110-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -111 -Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -112-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -113-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -114-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -115-Docket No.: 183B-412969-WO*** = < 1 nM** = 1 nM to 100 nM* = > 100 nMA = > 80% EmaxB = 50 - 80% EmaxC = < 50% EmaxAgonist activity of melanocortin analogs on melanocortin 3 receptor and melanocortin 4 receptor

[0303] 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 13).Table 13. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and the melanocortin 4 receptor (MC4R)SMRH:4906-9094-6395 -116-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -117-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -118-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -119-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -120-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -121 -Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -122-Docket No.: 183B-412969-WO** = 1 nM to 100 nM* = > 100 nMA = > 80% EmaxB = 50 - 80% EmaxC = < 50% EmaxAntagonist activity of melanocortin analogs on melanocortin 3 receptor and melanocortin 4 receptor

[0304] Administration of none of the non-naturally occurring melanocortin analogs inhibited melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) activity, as measured by cAMP levels (Table 14).Table 14. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and the melanocortin 4 receptor (MC4R)SMRH:4906-9094-6395 -123-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -124-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -125-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -126-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -127-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -128-Docket No.: 183B-412969-WOSMRH:4906-9094-6395 -129-Docket No.: 183B-412969-WO** = 1 nM to 100 nM* = > 100 nMA = > 80% EmaxB = 50 - 80% EmaxC = < 50% EmaxAdditional Embodiments

[0305] Various embodiments of the present technology are set forth below in paragraphs

[0306] to

[0399] :

[0306] 1 . A non-naturally occurring melanocortin analog comprising a sequence of Formula (I):R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4-Y5(I), wherein:R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Orn, Dab, Aad, Asp, and Glu;Y1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), oc- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;SMRH:4906-9094-6395 -130-Docket No.: 183B-412969-WOY3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp, Aad, or Glu and R7is Lys, Dab, or Orn, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu; provided that: when Y1is dVal, then Y2is dPro.

[0307] 2. The non-naturally occurring melanocortin analog of embodiment 1 , wherein:R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Orn, Dab, Aad, Asp, and Glu;Y1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;Y3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;SMRH:4906-9094-6395 -131 -Docket No.: 183B-412969-WOY4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp, Aad, or Glu and R7is Lys, Dab, or Orn, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 2);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 3);Ac-Nle-c[Glu-His-dPhe-Arg-Trp-Orn]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 4);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 5);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Nle-c[Orn-His-dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 8);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 9);Ac-Nle-c[Dab-His-dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 10);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 11 );Ac-Nle-c[Aad-His-dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 12); andAc-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 13), wherein c represents cyclization through a lactam bond between R2and R7.

[0308] 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-Y3-Y4- Y5( I A) , wherein:SMRH:4906-9094-6395 -132-Docket No.: 183B-412969-WOR1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is Orn;Y1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;Y3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp, Aad, or Glu and R7is Lys, Dab, or Orn, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu; provided that: when Y1is dVal, then Y2is dPro.

[0309] 4. The non-naturally occurring melanocortin analog of any one of embodiments 1 -3, wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);SMRH:4906-9094-6395 -133-Docket No.: 183B-412969-WOR5is arginine (Arg);R6is tryptophan (Trp);R7is Orn;Y1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;Y3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 5), wherein c represents cyclization through a lactam bond between R2and R7.

[0310] 5. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, wherein the sequence of Formula (I) or (IA) is a sequence of Formula (IA(i)):R1- R2- R3- R4- R5- R6-R7-Y1-Y2-Y3-Y4-Y5( I A(i)) , wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);SMRH:4906-9094-6395 -134-Docket No.: 183B-412969-WOR7is ornithine (Orn);Y1is D-valine (dVal);Y2is D-proline (dPro);Y3is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), Asp, oc-phenylglycine (Phg), D-oc-phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y4is absent or is selected from the group consisting of dSer, dPhe, Phg, dPhg, Asp, Orn, dOrn, dAsp, dNIe, dAla, and Gly;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0311] 6. The non-naturally occurring melanocortin analog of any one of embodiments 1 -5, wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is D-valine (dVal);Y2is D-proline (dPro);Y3is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), D-alanine (dAla), and glycine (Gly);Y4is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, dAla, and Gly;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe; andSMRH:4906-9094-6395 -135-Docket No.: 183B-412969-WO the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0312] 7. The non-naturally occurring melanocortin analog of any one of embodiments 1 -5, wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is D-valine (dVal);Y2is D-proline (dPro);Y3is selected from the group consisting of Asp, oc-phenylglycine (Phg), D-oc- phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y4is absent or is selected from the group consisting of Phg, dPhg, Asp, and Orn;Y5is absent; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0313] 8. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, wherein the sequence of Formula (I) or (IA) is a sequence of Formula (IA(ii)):R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4-Y5(IA(ii)), wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);SMRH:4906-9094-6395 -136-Docket No.: 183B-412969-WOR7is ornithine (Orn);Y1is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), Asp, oc-phenylglycine (Phg), D-oc-phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-valine (dVal), dSer, dPhe, dOrn, dAsp, dNIe, Asp, Phg, dPhg, Orn, dAla, and Gly;Y3is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, dOrn, dAsp, dNIe, Asp, Phg, dPhg, and Orn;Y4is absent, dPro, or dVal;Y5is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0314] 9. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4 and 8, wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-valine (dVal), dSer, dPhe, dOrn, dAsp, dNIe, dAla, and Gly;Y3is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, dOrn, dAsp, and dNIe;Y4is absent, dPro, or dVal;Y5is absent or dPro; andSMRH:4906-9094-6395 -137-Docket No.: 183B-412969-WO the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0315] 10. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, and 9, wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is selected from the group consisting of Asp, oc-phenylglycine (Phg), D-oc- phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-valine (dVal), Asp, Phg, dPhg, Orn, dAla, and Gly;Y3is selected from the group consisting of D-proline (dPro), dVal, Asp, Phg, dPhg, and Orn;Y4is absent, dPro, or dVal;Y5is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0316] 11. The non-naturally occurring melanocortin analog of embodiment 1 or 2, wherein the sequence of Formula (I) is a sequence of Formula (IB):R1- R2- R3- R4- R5- R6- R7- Y1-Y2-Y3-Y4-Y5(IB), wherein:R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);SMRH:4906-9094-6395 -138-Docket No.: 183B-412969-WOR5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Dab, Aad, Asp, and glutamic acid(Glu);Y1is selected from the group consisting of D-valine (dVal), D-ornithine (dOrn), D- alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dOrn, dAla, and Gly;Y3is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y4is absent or is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y5is absent, dOrn, or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp or Aad and R7is Lys or Dab, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu, provided that: when Y1is dVal, then Y2is dPro.

[0317] 12. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, and 1 1 , wherein:R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Dab, Aad, Asp, and glutamic acid (Glu);Y1is selected from the group consisting of D-valine (dVal), D-ornithine (dOrn), D- alanine (dAla), and glycine (Gly);SMRH:4906-9094-6395 -139-Docket No.: 183B-412969-WOY2is selected from the group consisting of D-proline (dPro), dVal, dOrn, dAla, and Gly;Y3is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y4is absent or is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y5is absent, dOrn, or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp or Aad and R7is Lys or Dab, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 2);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 3);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Nle-c[Orn-His-dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 8);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 9);Ac-Nle-c[Dab-His-dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 10);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 11 );Ac-Nle-c[Aad-His-dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 12); andAc-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 13), wherein c represents cyclization through a lactam bond between R2and R7.

[0318] 13. The non-naturally occurring melanocortin analog of any one of embodiments 1 -12, wherein the N-terminus of the sequence of any one of Formulae (l)-(IB) is acylated.SMRH:4906-9094-6395 -140-Docket No.: 183B-412969-WO

[0319] 14. The non-naturally occurring melanocortin analog of any one of embodiments 1 -13, wherein the N-terminus of the sequence of any one of Formulae (l)-(IB) is acetylated.

[0320] 15. The non-naturally occurring melanocortin analog of any one of embodiments 1 -12, wherein the N-terminus of the sequence of any one of Formulae (l)-(IB) is not modified.

[0321] 16. The non-naturally occurring melanocortin analog of any one of embodiments 1 -15, wherein the C-terminus of the sequence of any one of Formulae (l)-(IB) is amidated.

[0322] 17. The non-naturally occurring melanocortin analog of any one of embodiments 1 -15, wherein the C-terminus of the sequence of any one of Formulae (l)-(IB) is not modified.

[0323] 18. The non-naturally occurring melanocortin analog of embodiment 1 or 2, wherein the sequence of Formula (I) is cyclized via a lactam bond between Glu at R2and Orn at R7.

[0324] 19. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4 and 13-18, wherein: Y1is dVal; and Y2is dPro.

[0325] 20. The non-naturally occurring melanocortin analog of any one of embodiments 1 -5, and 13-19, wherein Y4and Y5are absent.

[0326] 21 . The non-naturally occurring melanocortin analog of any one of embodiments 1 -5 and 13-20, wherein Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0327] 22. The non-naturally occurring melanocortin analog of any one of embodiments 1 -6 and 13-21 , wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-NH2(SEQ ID NO: 14); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-NH2(SEQ ID NO: 15); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-NH2 (SEQ ID NO: 16);SMRH:4906-9094-6395 -141 -Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-NH2(SEQ ID NO: 17); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-NH2(SEQ ID NO: 18), wherein c represents cyclization through R2and R7via a lactam bond.

[0328] 23. The non-naturally occurring melanocortin analog of any one of embodiments 1 -5, 7, and 13-20, wherein Y3is selected from the group consisting of Phg, dPhg, Asp, and Orn.

[0329] 24. The non-naturally occurring melanocortin analog of any one of embodiments 1 -5, 7, 13-20, and 23, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Phg-NH2(SEQ ID NO: 19);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhg-NH2(SEQ ID NO: 20);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Asp-NH2(SEQ ID NO: 21 ); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Orn-NH2(SEQ ID NO: 22), wherein c represents cyclization through R2and R7via a lactam bond.

[0330] 25. The non-naturally occurring melanocortin analog of any one of embodiments 1 -5 and 13-19, wherein: Y3is dAla or Gly; and Y5is absent.

[0331] 26. The non-naturally occurring melanocortin analog of any one of embodiments 1 -5, 13-19, and 25, wherein Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0332] 27. The non-naturally occurring melanocortin analog of any one of embodiments 1 -6, 13-19, 25, and 26, wherein the sequence of any one of Formulae (I)- (IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-NH2(SEQ ID NO: 23);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-NH2(SEQ ID NO: 24);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 25);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-NH2(SEQ ID NO: 26); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-NH2(SEQ ID NO: 27); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dSer-NH2(SEQ ID NO: 28);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dPhe-NH2(SEQ ID NO: 29);SMRH:4906-9094-6395 -142-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 30);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dAsp-NH2(SEQ ID NO: 31 ); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dNle-NH2(SEQ ID NO: 32), wherein c represents cyclization through R2and R7via a lactam bond.

[0333] 28. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 7, 13-19, and 25, wherein Y4is selected from the group consisting of Phg, dPhg, Asp, and Orn.

[0334] 29. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 7, 13-19, 25, and 28, wherein the sequence of any one of Formulae (I)- (IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-Phg-NH2(SEQ ID NO: 33);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhg-NH2(SEQ ID NO: 34);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-Asp-NH2(SEQ ID NO: 35);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-Orn-NH2(SEQ ID NO: 36);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Phg-NH2(SEQ ID NO: 37);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dPhg-NH2(SEQ ID NO: 38);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Asp-NH2(SEQ ID NO: 39); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Orn-NH2(SEQ ID NO: 40), wherein c represents cyclization through R2and R7via a lactam bond.

[0335] 30. The non-naturally occurring melanocortin analog of any one of embodiments 1 -6, and 13-19, wherein Y3is dAla or Gly; and Y4is dAla or Gly.

[0336] 31. The non-naturally occurring melanocortin analog of any one of embodiments 1 -6, 13-19, and 30, wherein Y5is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0337] 32. The non-naturally occurring melanocortin analog of any one of embodiments 1 -6, 13-19, 30, and 31 , wherein the sequence of any one of Formulae (I)- (IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dSer-NH2(SEQ ID NO: 66); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dPhe-NH2(SEQ ID NO: 67);SMRH:4906-9094-6395 -143-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 68); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dAsp-NH2(SEQ ID NO: 69); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dNle-NH2(SEQ ID NO: 70);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dSer-NH2(SEQ ID NO: 71 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dPhe-NH2(SEQ ID NO: 72); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 73);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dAsp-NH2(SEQ ID NO: 74); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dNle-NH2(SEQ ID NO: 75), wherein c represents cyclization through R2and R7via a lactam bond.

[0338] 33. The non-naturally occurring melanocortin analog of any one of embodiments 1 -6 and 13-19, wherein Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0339] 34. The non-naturally occurring melanocortin analog of any one of embodiments 1 -6, 13-19, and 33, wherein: Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe; and Y5is absent.

[0340] 35. The non-naturally occurring melanocortin analog of any one of embodiments 1 -6, 13-19, 33, and 34, wherein the sequence of any one of Formulae (I)- (IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dSer-NH2(SEQ ID NO: 41 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dPhe-NH2(SEQ ID NO: 42); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dOrn-NH2(SEQ ID NO: 43);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dAsp-NH2(SEQ ID NO: 44); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dNle-NH2(SEQ ID NO: 45); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dSer-NH2(SEQ ID NO: 46);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dPhe-NH2(SEQ ID NO: 47); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dOrn-NH2(SEQ ID NO: 48); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dAsp-NH2(SEQ ID NO: 49);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dNle-NH2(SEQ ID NO: 50); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dSer-NH2(SEQ ID NO: 51 );SMRH:4906-9094-6395 -144-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dPhe-NH2 (SEQ ID NO: 52);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dOrn-NH2 (SEQ ID NO: 53);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dAsp-NH2 (SEQ ID NO: 54);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dNle-NH2 (SEQ ID NO: 55);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dSer-NH2 (SEQ ID NO: 56);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dPhe-NH2 (SEQ ID NO: 57);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dOrn-NH2 (SEQ ID NO: 58);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dAsp-NH2 (SEQ ID NO: 59);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dNle-NH2 (SEQ ID NO: 60);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dSer-NH2 (SEQ ID NO: 61 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dPhe-NH2 (SEQ ID NO: 62);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dOrn-NH2 (SEQ ID NO: 63);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dAsp-NH2 (SEQ ID NO: 64); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dNle-NH2 (SEQ ID NO: 65), wherein c represents cyclization through R2and R7via a lactam bond.

[0341] 36. The non-naturally occurring melanocortin analog of any one of embodiments 1 -6, 13-19, and 33, wherein:Y3is dAla; andY5is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0342] 37. The non-naturally occurring melanocortin analog of any one of embodiments 1 -6, 13-19, 33, and 36, wherein the sequence of any one of Formulae (I)- (IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dSer-NH2(SEQ ID NO: 76);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dPhe-NH2(SEQ ID NO: 77);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dOrn-NH2 (SEQ ID NO: 78);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dAsp-NH2(SEQ ID NO: 79);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dNle-NH2(SEQ ID NO: 80);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dSer-NH2(SEQ ID NO: 81 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dPhe-NH2(SEQ ID NO: 82);SMRH:4906-9094-6395 -145-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dOrn-NH2(SEQ ID NO:83);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dAsp-NH2(SEQ ID NO:84);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dNle-NH2(SEQ ID NO: 85);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dSer-NH2(SEQ ID NO: 86);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dPhe-NH2(SEQ ID NO: 87);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dOrn-NH2(SEQ ID NO: 88);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dAsp-NH2(SEQ ID NO:184);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dNle-NH2(SEQ ID NO:185);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dSer-NH2(SEQ ID NO:186);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dPhe-NH2(SEQ ID NO:187);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dOrn-NH2(SEQ ID NO:188);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dAsp-NH2(SEQ ID NO:189);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dNle-NH2(SEQ ID NO:190);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dSer-NH2(SEQ ID NO:191 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dPhe-NH2(SEQ ID NO:192);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dOrn-NH2(SEQ ID NO:193);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dAsp-NH2(SEQ ID NO:194); andSMRH:4906-9094-6395 -146-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dNle-NH2(SEQ ID NO: 195), wherein c represents cyclization through R2and R7via a lactam bond.

[0343] 38. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, and 13-18, wherein Y2is dVal; Y3is dPro; and Y4and Y5are absent.

[0344] 39. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 9, 13-18, and 38, wherein Y1is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0345] 40. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 9, 13-18, 38, and 39, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dVal-dPro-NH2(SEQ ID NO: 89);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dVal-dPro-NH2(SEQ ID NO: 90);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dVal-dPro-NH2(SEQ ID NO: 91 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dVal-dPro-NH2(SEQ ID NO: 92); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dVal-dPro-NH2(SEQ ID NO: 93), wherein c represents cyclization through R2and R7via a lactam bond.

[0346] 41. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 10, 13-18, and 38, wherein Y1is selected from the group consisting of Phg, dPhg, Asp, and Orn.

[0347] 42. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 10, 13-18, and 41 , wherein the sequence of any one of Formulae (I)- (IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Phg-dVal-dPro-NH2(SEQ ID NO: 94);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhg-dVal-dPro-NH2(SEQ ID NO: 95);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Asp-dVal-dPro-NH2(SEQ ID NO: 96); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Orn-dVal-dPro-NH2(SEQ ID NO: 97), wherein c represents cyclization through R2and R7via a lactam bond.SMRH:4906-9094-6395 -147-Docket No.: 183B-412969-WO

[0348] 43. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, and 13-18, wherein: Y3is dVal; and Y4is dPro.

[0349] 44. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 9, 13-18, and 43, wherein Y2is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0350] 45. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 9, 13-18, 43, and 44, wherein Y1is dAla or Gly.

[0351] 46. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 9, 13-18, and 43-45, wherein the sequence of any one of Formulae (I)- (IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dVal-dPro-NH2(SEQ ID NO: 98); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dVal-dPro-NH2(SEQ ID NO: 99); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 100);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 101 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dVal-dPro-NH2(SEQ ID NO: 102); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dSer-dVal-dPro-NH2(SEQ ID NO: 103);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dPhe-dVal-dPro-NH2(SEQ ID NO: 104); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 105); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 106); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dNle-dVal-dPro-NH2(SEQ ID NO: 107), wherein c represents cyclization through R2and R7via a lactam bond.

[0352] 47. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 9, 13-18, 43, and 44, wherein Y1is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0353] 48. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 9, 13-18, 43, 44, and 47, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dSer-dVal-dPro-NH2(SEQ ID NO: 116); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dPhe-dVal-dPro-NH2(SEQ ID NO: 1 17);SMRH:4906-9094-6395 -148-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dOrn-dVal-dPro-NH2(SEQ ID NO: 118);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dAsp-dVal-dPro-NH2(SEQ ID NO: 1 19);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dNle-dVal-dPro-NH2(SEQ ID NO: 120);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dSer-dVal-dPro-NH2(SEQ ID NO: 121 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dPhe-dVal-dPro-NH2(SEQ ID NO: 122);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dOrn-dVal-dPro-NH2(SEQ ID NO: 123);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dAsp-dVal-dPro-NH2(SEQ ID NO: 124);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dNle-dVal-dPro-NH2(SEQ ID NO: 125);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dSer-dVal-dPro-NH2(SEQ ID NO: 126);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dPhe-dVal-dPro-NH2(SEQ ID NO: 127);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dOrn-dVal-dPro-NH2(SEQ ID NO: 128);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dAsp-dVal-dPro-NH2(SEQ ID NO: 129);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dNle-dVal-dPro-NH2(SEQ ID NO: 130);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dSer-dVal-dPro-NH2(SEQ ID NO: 131 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dPhe-dVal-dPro-NH2(SEQ ID NO: 132);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dOrn-dVal-dPro-NH2(SEQ ID NO: 133);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dAsp-dVal-dPro-NH2(SEQ ID NO: 134);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dNle-dVal-dPro-NH2(SEQ ID NO: 135);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dSer-dVal-dPro-NH2(SEQ ID NO: 136);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dPhe-dVal-dPro-NH2(SEQ ID NO: 137);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dOrn-dVal-dPro-NH2(SEQ ID NO: 138);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dAsp-dVal-dPro-NH2(SEQ ID NO: 139); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dNle-dVal-dPro-NH2(SEQ ID NO: 140), wherein c represents cyclization through R2and R7via a lactam bond.

[0354] 49. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 10, 13-18, and 43, wherein Y2is selected from the group consisting of Phg, dPhg, Asp, and Orn.

[0355] 50. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 10, 13-18, 43, and 49, wherein Y1is dAla or Gly.SMRH:4906-9094-6395 -149-Docket No.: 183B-412969-WO

[0356] 51. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 10, 13-18, 43, 49, and 50, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-Phg-dVal-dPro-NH2(SEQ ID NO: 108); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhg-dVal-dPro-NH2(SEQ ID NO: 109); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Phg-dVal-dPro-NH2(SEQ ID NO: 1 10); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dPhg-dVal-dPro-NH2(SEQ ID NO: 111 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-Asp-dVal-dPro-NH2(SEQ ID NO: 112); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Asp-dVal-dPro-NH2(SEQ ID NO: 1 13); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-Orn-dVal-dPro-NH2(SEQ ID NO: 114); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Orn-dVal-dPro-NH2(SEQ ID NO: 115), wherein c represents cyclization through R2and R7via a lactam bond.

[0357] 52. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4and 13-18, wherein: Y4is dVal; and Y5is dPro.

[0358] 53. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 13-18, and 52, wherein Y1is dAla or Gly.

[0359] 54. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 9, 13-18, 52, and 53, wherein Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0360] 55. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 9, 13-18, and 52-54, wherein Y2is dAla and Gly.

[0361] 56. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 9, 13-18, and 52-55, wherein the sequence of any one of Formulae (I)- (IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dSer-dVal-dPro-NH2(SEQ ID NO:141 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dPhe-dVal-dPro-NH2(SEQ ID NO:142);SMRH:4906-9094-6395 -150-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO:143);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO:144);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dNle-dVal-dPro-NH2(SEQ ID NO:145);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dSer-dVal-dPro-NH2(SEQ ID NO: 146); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dPhe-dVal-dPro-NH2(SEQ ID NO: 147); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 148);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 149); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dNle-dVal-dPro-NH2(SEQ ID NO: 150), wherein c represents cyclization through R2and R7via a lactam bond.

[0362] 57. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 9, 13-18, and 52-54, wherein Y2is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

[0363] 58. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 9, 13-18, 52-54, and 57, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dSer-dVal-dPro-NH2(SEQ ID NO:159);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dPhe-dVal-dPro-NH2(SEQ ID NO:160);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dOrn-dVal-dPro-NH2(SEQ ID NO:161 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dAsp-dVal-dPro-NH2(SEQ ID NO:162);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dNle-dVal-dPro-NH2(SEQ ID NO:163);SMRH:4906-9094-6395 -151 -Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dSer-dVal-dPro-NH2 (SEQ ID NO:164);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dPhe-dVal-dPro-NH2(SEQ ID NO:165);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dOrn-dVal-dPro-NH2 (SEQ ID NO:166);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dAsp-dVal-dPro-NH2 (SEQ ID NO:167);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dNle-dVal-dPro-NH2 (SEQ ID NO:168);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dSer-dVal-dPro-NH2 (SEQ ID NO:169);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dPhe-dVal-dPro-NH2 (SEQ ID NO:1 0);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dOrn-dVal-dPro-NH2 (SEQ ID NO:171 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dAsp-dVal-dPro-NH2 (SEQ ID NO:172);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dNle-dVal-dPro-NH2 (SEQ ID NO:173);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dSer-dVal-dPro-NH2 (SEQ ID NO:174);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dPhe-dVal-dPro-NH2 (SEQ ID NO:175);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dOrn-dVal-dPro-NH2 (SEQ ID NO:176);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dAsp-dVal-dPro-NH2 (SEQ ID NO:177);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dNle-dVal-dPro-NH2 (SEQ ID NO:178);SMRH:4906-9094-6395 -152-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dSer-dVal-dPro-NH2 (SEQ ID NO:179);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dPhe-dVal-dPro-NH2(SEQ ID NO:180);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dOrn-dVal-dPro-NH2 (SEQ ID NO:181 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dAsp-dVal-dPro-NH2 (SEQ ID NO:182); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dNle-dVal-dPro-NH2 (SEQ ID NO:183), wherein c represents cyclization through R2and R7via a lactam bond.

[0364] 59. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 10, 13-18, 52, and 53, wherein Y3is selected from the group consisting of Phg, dPhg, Asp, and Orn.

[0365] 60. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 10, 13-18, 52, 53, and 59, wherein Y2is dAla and Gly.

[0366] 61. The non-naturally occurring melanocortin analog of any one of embodiments 1 -4, 8, 10, 13-18, 52, 53, 59, and 60, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-Phg-dVal-dPro-NH2(SEQ ID NO: 151 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dPhg-dVal-dPro-NH2(SEQ ID NO: 152);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-Phg-dVal-dPro-NH2(SEQ ID NO: 153); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dPhg-dVal-dPro-NH2(SEQ ID NO: 154); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-Asp-dVal-dPro-NH2(SEQ ID NO: 155);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-Asp-dVal-dPro-NH2(SEQ ID NO: 156); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-Orn-dVal-dPro-NH2 (SEQ ID NO: 157); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-Orn-dVal-dPro-NH2 (SEQ ID NO: 158), wherein c represents cyclization through R2and R7via a lactam bond.SMRH:4906-9094-6395 -153-Docket No.: 183B-412969-WO

[0367] 62. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, and 11 -22, wherein the sequence of Formula (I) or (IB) is cyclized via a lactam bond between Orn at R2and Glu at R7.

[0368] 63. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, 11 -22, and 68, wherein the sequence of Formula (I) or (IB) is selected from the group consisting of: Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dOrn-dVal-dPro-NH2 (SEQ ID NO: 230);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 231 ); Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 232); Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO:233);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 234); Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-dOrn-NH2(SEQ ID NO: 235); Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 236);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 237);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 238); andAc-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 239), wherein c represents cyclization through R2and R7via a lactam bond.

[0369] 64. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, and 11 -22, wherein the sequence of Formula (I) or (IB) is cyclized via a lactam bond between Asp at R2and Lys at R7.

[0370] 65. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, 11 -22, and 70, wherein R4is p(F)dPhe.

[0371] 66. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, 11 -22, 64, and 65, wherein the sequence of Formula (I) or (IB) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dOrn-dVal-dPro-NH2(SEQ ID NO: 200);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 201 ); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 202);SMRH:4906-9094-6395 -154-Docket No.: 183B-412969-WOAc-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 203);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 204); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-dOrn-NH2(SEQ ID NO: 205); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 206);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 207);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 208); andAc-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 209), wherein c represents cyclization through R2and R7via a lactam bond.

[0372] 67. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, 11 -22, and 64, wherein R4is dPhe.

[0373] 68. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, 11 -22, 64, and 67, wherein the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAsp-dVal-dPro-NH2(SEQ ID NO: 196);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dOrn-dVal-dPro-NH2(SEQ ID NO: 197);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 198); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 199); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 250);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 251 ); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 252); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 253); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 254); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 255); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dAsp-NH2(SEQ ID NO: 256);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dOrn-NH2(SEQ ID NO: 257);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dAsp-NH2(SEQ ID NO: 258); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 259); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-dAsp-NH2(SEQ ID NO: 260); andSMRH:4906-9094-6395 -155-Docket No.: 183B-412969-WOAc-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 261 ); wherein c represents cyclization through R2and R7via a lactam bond.

[0374] 69. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, and 11 -22, wherein the sequence of Formula (I) or (IB) is cyclized via a lactam bond between Lys at R2and Asp at R7.

[0375] 70. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, 11 -22, and 69, wherein R4is p(F)dPhe.

[0376] 71. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, 11 -22, 69, and 70, wherein the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dOrn-dVal-dPro-NH2(SEQ ID NO: 220);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 221 ); Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 222);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 223);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 224); Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-dOrn-NH2(SEQ ID NO: 225);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 226); Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 227);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 228); andAc-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 229), wherein c represents cyclization through R2and R7via a lactam bond.

[0377] 72. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, 11 -22, and 69, wherein R4is dPhe.

[0378] 73. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, 11 -22, 69, and 72, wherein the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAsp-dVal-dPro-NH2(SEQ ID NO: 262);SMRH:4906-9094-6395 -156-Docket No.: 183B-412969-WOAc-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dOrn-dVal-dPro-NH2(SEQ ID NO: 263);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dAsp-dVal-dPro-NH2 (SEQ ID NO: 264);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 265);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-dAsp-dVal-dPro-NH2 (SEQ ID NO: 266);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 267);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dAla-dAsp-dVal-dPro-NH2 (SEQ ID NO: 268);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 269);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 270);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 271 );Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dAsp-NH2(SEQ ID NO: 272);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dOrn-NH2(SEQ ID NO: 273);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dAsp-NH2 (SEQ ID NO: 274);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 275);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-dAsp-NH2 (SEQ ID NO: 276); and Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 277), wherein c represents cyclization through R2and R7via a lactam bond.

[0379] 74. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, and 11 -22, wherein the sequence of Formula (I) or (IB) is cyclized via a lactam bond between Aad at R2and Dab at R7.

[0380] 75. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, 11 -22, and 74, wherein the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dOrn-dVal-dPro-NH2(SEQ ID NO: 210);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 211 );Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 212);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 213);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 214); Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-dOrn-NH2(SEQ ID NO: 215);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 216);SMRH:4906-9094-6395 -157-Docket No.: 183B-412969-WOAc-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-Gly-dOrn-NH2 (SEQ ID NO: 217);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 218); andAc-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-Gly-Gly-dOm-NH2(SEQ ID NO: 219), wherein c represents cyclization through R2and R7via a lactam bond.

[0381] 76. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, and 11 -22, wherein the sequence of Formula (I) or (IB) is cyclized via a lactam bond between Dab at R2and Aad at R7.

[0382] 77. The non-naturally occurring melanocortin analog of any one of embodiments 1 , 2, 11 -22, and 76, wherein the sequence of Formula (I) or (IB) is selected from the group consisting of: Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dOrn-dVal-dPro-NH2(SEQ ID NO: 240);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 241 ); Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 242);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 243);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 244); Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-dOrn-NH2(SEQ ID NO: 245);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 246); Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 247);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 248); andAc-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 249), wherein c represents cyclization through R2and R7via a lactam bond.

[0383] 78. The non-naturally occurring melanocortin analog of any one of embodiments 1 -77, wherein the non-naturally occurring melanocortin analog is present in a pharmaceutical composition.

[0384] 79. The non-naturally occurring melanocortin analog of embodiment 78, wherein the pharmaceutical composition further comprises a pharmaceutical salt.SMRH:4906-9094-6395 -158-Docket No.: 183B-412969-WO

[0385] 80. The non-naturally occurring melanocortin analog of embodiment 78, wherein the pharmaceutical composition further comprises a pharmaceutical carrier.

[0386] 81. The non-naturally occurring melanocortin analog of embodiment 80, wherein the pharmaceutical carrier comprises water.

[0387] 82. The non-naturally occurring melanocortin analog of embodiment 78, 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.

[0388] 83. The non-naturally occurring melanocortin analog of embodiment 78, 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.

[0389] 84. The non-naturally occurring melanocortin analog of embodiment 78, 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.

[0390] 85. The non-naturally occurring melanocortin analog of any one of embodiments 1 -84, wherein the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

[0391] 86. The non-naturally occurring melanocortin analog of any one of embodiments 78-85, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally.

[0392] 87. The non-naturally occurring melanocortin analog of any one of embodiments 78-86, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.

[0393] 88. The non-naturally occurring melanocortin analog of any one of embodiments 1 -87, wherein the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of the subject.

[0394] 89. The non-naturally occurring melanocortin analog of any one of embodiments 1 -88, wherein the therapeutically effective amount of the non-naturallySMRH:4906-9094-6395 -159-Docket No.: 183B-412969-WO occurring melanocortin analog is from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

[0395] 90. The non-naturally occurring melanocortin analog of any one of embodiments 1 -89, 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.

[0396] 91. The non-naturally occurring melanocortin analog of any one of embodiments 1 -90, 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.

[0397] 92. The non-naturally occurring melanocortin analog of any one of embodiments 1 -91 , 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.

[0398] 93. The non-naturally occurring melanocortin analog of any one of embodiments 1 -92, 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.

[0399] 94. The non-naturally occurring melanocortin analog of any one of embodiments 1 -98, 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.

[0400] 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.SMRH:4906-9094-6395 -160-

Claims

Docket No.: 183B-412969-WOCLAIMS l / We claim:

1. A non-naturally occurring melanocortin analog comprising a sequence of Formula (I):R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4-Y5(I), wherein:R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Orn, Dab, Aad, Asp, and Glu;Y1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;Y3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp, Aad, or Glu and R7is Lys, Dab, or Orn, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu;SMRH:4906-9094-6395 -161 -Docket No.: 183B-412969-WO provided that: when Y1is dVal, then Y2is dPro.

2. The non-naturally occurring melanocortin analog of claim 1 , wherein:R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), glutamic acid (Glu), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Orn, Dab, Aad, Asp, and Glu;Y1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;Y3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp, Aad, or Glu and R7is Lys, Dab, or Orn, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 2);SMRH:4906-9094-6395 -162-Docket No.: 183B-412969-WOAc-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 3);Ac-Nle-c[Glu-His-dPhe-Arg-Trp-Orn]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 4);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 5);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Nle-c[Orn-His-dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 8);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 9);Ac-Nle-c[Dab-His-dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 10);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 11 );Ac-Nle-c[Aad-His-dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 12); andAc-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 13), wherein c represents cyclization through a lactam bond between R2and R7.

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-Y3-Y4- Y5( I A) , wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is Orn;Y1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);SMRH:4906-9094-6395 -163-Docket No.: 183B-412969-WOY2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;Y3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp, Aad, or Glu and R7is Lys, Dab, or Orn, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu; provided that: when Y1is dVal, then Y2is dPro.

4. The non-naturally occurring melanocortin analog of any one of claims 1 -3, wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is Orn;Y1is selected from the group consisting of D-valine (dVal), dPhe, D-serine (dSer), D- norleucine (dNIe), Asp, D-aspartic acid (dAsp), ornithine (Orn), D-ornithine (dOrn), a- phenylglycine (Phg), D-oc-phenylglycine (dPhg), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, Phg, dPhg, dAla, and Gly;SMRH:4906-9094-6395 -164-Docket No.: 183B-412969-WOY3is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y4is absent or is selected from the group consisting of dSer, dPhe, Orn, dOrn, Asp, dAsp, dNIe, dAla, Gly, dPro, dVal, Phg, and dPhg;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, and dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 5), wherein c represents cyclization through a lactam bond between R2and R7.

5. The non-naturally occurring melanocortin analog of any one of claims 1 -4, wherein the sequence of Formula (I) or (IA) is a sequence of Formula (I A(i)) :R1- R2- R3- R4- R5- R6- R7- Y1-Y2- Y3- Y4-Y5( I A ( i ) ) , wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is D-valine (dVal);Y2is D-proline (dPro);Y3is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), Asp, oc-phenylglycine (Phg), D-oc-phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y4is absent or is selected from the group consisting of dSer, dPhe, Phg, dPhg, Asp, Orn, dOrn, dAsp, dNIe, dAla, and Gly;SMRH:4906-9094-6395 -165-Docket No.: 183B-412969-WOY5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

6. The non-naturally occurring melanocortin analog of any one of claims 1 -5, wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is D-valine (dVal);Y2is D-proline (dPro);Y3is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), D-alanine (dAla), and glycine (Gly);Y4is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, dNIe, dAla, and Gly;Y5is absent or is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

7. The non-naturally occurring melanocortin analog of any one of claims 1 -5, wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);SMRH:4906-9094-6395 -166-Docket No.: 183B-412969-WOR3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is D-valine (dVal);Y2is D-proline (dPro);Y3is selected from the group consisting of Asp, oc-phenylglycine (Phg), D-oc- phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y4is absent or is selected from the group consisting of Phg, dPhg, Asp, and Orn;Y5is absent; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

8. The non-naturally occurring melanocortin analog of any one of claims 1 -4, wherein the sequence of Formula (I) or (IA) is a sequence of Formula (IA(ii)):R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4-Y5(IA(ii)), wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), Asp, oc-phenylglycine (Phg), D-oc-phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-valine (dVal), dSer, dPhe, dOrn, dAsp, dNIe, Asp, Phg, dPhg, Orn, dAla, and Gly;SMRH:4906-9094-6395 -167-Docket No.: 183B-412969-WOY3is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, dOrn, dAsp, dNIe, Asp, Phg, dPhg, and Orn;Y4is absent, dPro, or dVal;Y5is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

9. The non-naturally occurring melanocortin analog of any one of claims 1 -4 and 8, wherein:R1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is selected from the group consisting of D-serine (dSer), D-phenylalanine (dPhe), D-ornithine (dOrn), D-aspartic acid (dAsp), D-norleucine (dNIe), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-valine (dVal), dSer, dPhe, dOrn, dAsp, dNIe, dAla, and Gly;Y3is selected from the group consisting of D-proline (dPro), dVal, dSer, dPhe, dOrn, dAsp, and dNIe;Y4is absent, dPro, or dVal;Y5is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.

10. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, and 9, wherein:SMRH:4906-9094-6395 -168-Docket No.: 183B-412969-WOR1is norleucine (Nle);R2is glutamic acid (Glu);R3is histidine (His);R4is parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is ornithine (Orn);Y1is selected from the group consisting of Asp, oc-phenylglycine (Phg), D-oc- phenylglycine (dPhg), ornithine (Orn), D-alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-valine (dVal), Asp, Phg, dPhg, Orn, dAla, and Gly;Y3is selected from the group consisting of D-proline (dPro), dVal, Asp, Phg, dPhg, and Orn;Y4is absent, dPro, or dVal;Y5is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between Glu at R2and Orn at R7.1 1 . 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-Y3-Y4-Y5(IB), wherein:R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);SMRH:4906-9094-6395 -169-Docket No.: 183B-412969-WOR7is selected from the group consisting of Lys, Dab, Aad, Asp, and glutamic acid (Glu);Y1is selected from the group consisting of D-valine (dVal), D-ornithine (dOrn), D- alanine (dAla), and glycine (Gly);Y2is selected from the group consisting of D-proline (dPro), dVal, dOrn, dAla, and Gly;Y3is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y4is absent or is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y5is absent, dOrn, or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp or Aad and R7is Lys or Dab, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu, provided that: when Y1is dVal, then Y2is dPro.

12. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, and 1 1 , wherein:R1is norleucine (Nle);R2is selected from the group consisting of aspartic acid (Asp), aminoadipic acid (Aad), 2,4-diaminobutyric acid (Dab), lysine (Lys), and ornithine (Orn);R3is histidine (His);R4is D-phenylalanine (dPhe) or parafluoro-D-phenylalanine (p(F)dPhe);R5is arginine (Arg);R6is tryptophan (Trp);R7is selected from the group consisting of Lys, Dab, Aad, Asp, and glutamic acid (Glu);Y1is selected from the group consisting of D-valine (dVal), D-ornithine (dOrn), D- alanine (dAla), and glycine (Gly);SMRH:4906-9094-6395 -170-Docket No.: 183B-412969-WOY2is selected from the group consisting of D-proline (dPro), dVal, dOrn, dAla, and Gly;Y3is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y4is absent or is selected from the group consisting of dOrn, dAla, Gly, dPro, and dVal;Y5is absent, dOrn, or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between:R2and R7when R2is Asp or Aad and R7is Lys or Dab, orR2and R7when R2is Lys, Dab, or Orn and R7is Asp, Aad, or Glu, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 2);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 3);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Nle-c[Orn-His-dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 8);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 9);Ac-Nle-c[Dab-His-dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 10);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 11 );Ac-Nle-c[Aad-His-dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 12); andAc-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 13), wherein c represents cyclization through a lactam bond between R2and R7.

13. The non-naturally occurring melanocortin analog of any one of claims 1 -12, wherein the N-terminus of the sequence of any one of Formulae (l)-(IB) is acylated.SMRH:4906-9094-6395 -171 -Docket No.: 183B-412969-WO14. The non-naturally occurring melanocortin analog of any one of claims 1 -13, wherein the N-terminus of the sequence of any one of Formulae (l)-(IB) is acetylated.

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

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

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

18. The non-naturally occurring melanocortin analog of claim 1 or 2, wherein the sequence of Formula (I) is cyclized via a lactam bond between Glu at R2and Orn at R7.

19. The non-naturally occurring melanocortin analog of any one of claims 1 -4 and 13-18, wherein:Y1is dVal; andY2is dPro.

20. The non-naturally occurring melanocortin analog of any one of claims 1 -5, and 13-19, wherein Y4and Y5are absent.21 . The non-naturally occurring melanocortin analog of any one of claims 1 -5 and 13-20, wherein Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

22. The non-naturally occurring melanocortin analog of any one of claims 1 -6 and 13-21 , wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-NH2(SEQ ID NO: 14);SMRH:4906-9094-6395 -172-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-NH2(SEQ ID NO: 15); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-NH2(SEQ ID NO: 16); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-NH2(SEQ ID NO: 17); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-NH2(SEQ ID NO: 18), wherein c represents cyclization through R2and R7via a lactam bond.

23. The non-naturally occurring melanocortin analog of any one of claims 1 -5, 7, and 13-20, wherein Y3is selected from the group consisting of Phg, dPhg, Asp, and Orn.

24. The non-naturally occurring melanocortin analog of any one of claims 1 -5, 7, 13-20, and 23, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Phg-NH2(SEQ ID NO: 19);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhg-NH2(SEQ ID NO: 20); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Asp-NH2(SEQ ID NO: 21 ); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Orn-NH2(SEQ ID NO: 22), wherein c represents cyclization through R2and R7via a lactam bond.

25. The non-naturally occurring melanocortin analog of any one of claims 1 -5 and 13-19, wherein:Y3is dAla or Gly; andY5is absent.

26. The non-naturally occurring melanocortin analog of any one of claims 1 -5, 13- 19, and 25, wherein Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

27. The non-naturally occurring melanocortin analog of any one of claims 1 -6, 13- 19, 25, and 26, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-NH2(SEQ ID NO: 23);SMRH:4906-9094-6395 -173-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-NH2(SEQ ID NO: 24);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 25);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-NH2(SEQ ID NO: 26);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-NH2(SEQ ID NO: 27);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dSer-NH2(SEQ ID NO: 28);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dPhe-NH2(SEQ ID NO: 29);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 30);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dAsp-NH2(SEQ ID NO: 31 ); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dNle-NH2(SEQ ID NO: 32), wherein c represents cyclization through R2and R7via a lactam bond.

28. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 7, 13-19, and 25, wherein Y4is selected from the group consisting of Phg, dPhg, Asp, and Orn.

29. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 7, 13-19, 25, and 28, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-Phg-NH2(SEQ ID NO: 33);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhg-NH2(SEQ ID NO: 34);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-Asp-NH2(SEQ ID NO: 35);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-Orn-NH2(SEQ ID NO: 36);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Phg-NH2(SEQ ID NO: 37);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-dPhg-NH2(SEQ ID NO: 38);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Asp-NH2(SEQ ID NO: 39); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Orn-NH2(SEQ ID NO: 40), wherein c represents cyclization through R2and R7via a lactam bond.

30. The non-naturally occurring melanocortin analog of any one of claims 1 -6, and 13-19, wherein:Y3is dAla or Gly; and Y4is dAla or Gly.SMRH:4906-9094-6395 -174-Docket No.: 183B-412969-WO31 . The non-naturally occurring melanocortin analog of any one of claims 1 -6, 13- 19, and 30, wherein Y5is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

32. The non-naturally occurring melanocortin analog of any one of claims 1 -6, 13- 19, 30, and 31 , wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dSer-NH2 (SEQ ID NO: 66); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dPhe-NH2(SEQ ID NO: 67); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Om]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 68); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dAsp-NH2(SEQ ID NO: 69); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAla-dNle-NH2(SEQ ID NO: 70); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dSer-NH2(SEQ ID NO: 71 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dPhe-NH2(SEQ ID NO: 72); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dOrn-NH2 (SEQ ID NO: 73); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dAsp-NH2(SEQ ID NO: 74); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-Gly-Gly-dNle-NH2(SEQ ID NO: 75), wherein c represents cyclization through R2and R7via a lactam bond.

33. The non-naturally occurring melanocortin analog of any one of claims 1 -6 and 13-19, wherein Y4is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

34. The non-naturally occurring melanocortin analog of any one of claims 1 -6, 13- 19, and 33, wherein:Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe; and Y5is absent.SMRH:4906-9094-6395 -175-Docket No.: 183B-412969-WO35. The non-naturally occurring melanocortin analog of any one of claims 1 -6, 13- 19, 33, and 34, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dSer-NH2(SEQ ID NO: 41 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dPhe-NH2(SEQ ID NO: 42); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dOrn-NH2(SEQ ID NO: 43); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dAsp-NH2(SEQ ID NO: 44); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dSer-dNle-NH2(SEQ ID NO: 45); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dSer-NH2(SEQ ID NO: 46); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dPhe-NH2(SEQ ID NO: 47); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dOrn-NH2(SEQ ID NO: 48); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dAsp-NH2(SEQ ID NO: 49); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dPhe-dNle-NH2(SEQ ID NO: 50); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dSer-NH2(SEQ ID NO: 51 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dPhe-NH2(SEQ ID NO: 52); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dOrn-NH2(SEQ ID NO: 53); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dAsp-NH2(SEQ ID NO: 54); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dOrn-dNle-NH2(SEQ ID NO: 55); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dSer-NH2(SEQ ID NO: 56); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dPhe-NH2(SEQ ID NO: 57); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dOrn-NH2(SEQ ID NO: 58); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dAsp-NH2(SEQ ID NO: 59); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAsp-dNle-NH2(SEQ ID NO: 60); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dSer-NH2(SEQ ID NO: 61 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dPhe-NH2(SEQ ID NO: 62); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dOrn-NH2(SEQ ID NO: 63); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dAsp-NH2(SEQ ID NO: 64); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dNle-dNle-NH2(SEQ ID NO: 65), wherein c represents cyclization through R2and R7via a lactam bond.SMRH:4906-9094-6395 -176-Docket No.: 183B-412969-WO36. The non-naturally occurring melanocortin analog of any one of claims 1 -6, 13- 19, and 33, wherein:Y3is dAla; andY5is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

37. The non-naturally occurring melanocortin analog of any one of claims 1 -6, 13- 19, 33, and 36, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dSer-NH2 (SEQ ID NO: 76);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dPhe-NH2(SEQ ID NO: 77);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Om]-dVal-dPro-dAla-dSer-dOrn-NH2(SEQ ID NO: 78);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dAsp-NH2(SEQ ID NO: 79);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dSer-dNle-NH2(SEQ ID NO: 80);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dSer-NH2(SEQ ID NO: 81 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dPhe-NH2(SEQ ID NO:82);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dOrn-NH2 (SEQ ID NO:83);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dAsp-NH2(SEQ ID NO:84);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dPhe-dNle-NH2(SEQ ID NO: 85);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dSer-NH2 (SEQ ID NO: 86);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dPhe-NH2 (SEQ ID NO: 87);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dOrn-NH2 (SEQ ID NO: 88);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dAsp-NH2 (SEQ ID NO:184);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dOrn-dNle-NH2 (SEQ ID NO:185);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dSer-NH2(SEQ ID NO:186);SMRH:4906-9094-6395 -177-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dPhe-NH2(SEQ ID NO:187);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dOrn-NH2(SEQ ID NO:188);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dAsp-NH2(SEQ ID NO:189);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dAsp-dNle-NH2(SEQ ID NO:190);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dSer-NH2(SEQ ID NO:191 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dPhe-NH2(SEQ ID NO:192);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dOrn-NH2(SEQ ID NO:193);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dAsp-NH2(SEQ ID NO:194); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-dAla-dNle-dNle-NH2(SEQ ID NO:195), wherein c represents cyclization through R2and R7via a lactam bond.

38. The non-naturally occurring melanocortin analog of any one of claims 1 -4, and 13-18, whereinY2is dVal;Y3is dPro; andY4and Y5are absent.

39. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 9, 13-18, and 38, wherein Y1is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.SMRH:4906-9094-6395 -178-Docket No.: 183B-412969-WO40. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8,9, 13-18, 38, and 39, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dVal-dPro-NH2(SEQ ID NO: 89); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dVal-dPro-NH2(SEQ ID NO: 90); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dVal-dPro-NH2 (SEQ ID NO: 91 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dVal-dPro-NH2(SEQ ID NO: 92); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dVal-dPro-NH2(SEQ ID NO: 93), wherein c represents cyclization through R2and R7via a lactam bond.

41. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8,10, 13-18, and 38, wherein Y1is selected from the group consisting of Phg, dPhg, Asp, and Orn.

42. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 10, 13-18, and 41 , wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Phg-dVal-dPro-NH2(SEQ ID NO: 94); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhg-dVal-dPro-NH2(SEQ ID NO: 95); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Asp-dVal-dPro-NH2(SEQ ID NO: 96); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Orn-dVal-dPro-NH2 (SEQ ID NO: 97), wherein c represents cyclization through R2and R7via a lactam bond.

43. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, and 13-18, wherein:Y3is dVal; andY4is dPro.

44. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 9, 13-18, and 43, wherein Y2is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.SMRH:4906-9094-6395 -179-Docket No.: 183B-412969-WO45. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 9, 13-18, 43, and 44, wherein Y1is dAla or Gly.

46. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 9, 13-18, and 43-45, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dVal-dPro-NH2(SEQ ID NO: 98); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dVal-dPro-NH2(SEQ ID NO: 99); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 101 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dVal-dPro-NH2(SEQ ID NO: 102); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dSer-dVal-dPro-NH2(SEQ ID NO: 103); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dPhe-dVal-dPro-NH2(SEQ ID NO: 104); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dOrn-dVal-dPro-NH2 (SEQ ID NO: 105); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 106); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dNle-dVal-dPro-NH2(SEQ ID NO: 107), wherein c represents cyclization through R2and R7via a lactam bond.

47. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 9, 13-18, 43, and 44, wherein Y1is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

48. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 9, 13-18, 43, 44, and 47, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dSer-dVal-dPro-NH2(SEQ ID NO: 116); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dPhe-dVal-dPro-NH2(SEQ ID NO: 1 17); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dOrn-dVal-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dAsp-dVal-dPro-NH2(SEQ ID NO: 1 19); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dSer-dNle-dVal-dPro-NH2(SEQ ID NO: 120);SMRH:4906-9094-6395 -180-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dSer-dVal-dPro-NH2 (SEQ ID NO: 121 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dPhe-dVal-dPro-NH2(SEQ ID NO: 122);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dOrn-dVal-dPro-NH2 (SEQ ID NO: 123);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dAsp-dVal-dPro-NH2 (SEQ ID NO: 124);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dPhe-dNle-dVal-dPro-NH2 (SEQ ID NO: 125);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dSer-dVal-dPro-NH2 (SEQ ID NO: 126);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dPhe-dVal-dPro-NH2 (SEQ ID NO: 127);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dOrn-dVal-dPro-NH2 (SEQ ID NO: 128);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dAsp-dVal-dPro-NH2 (SEQ ID NO: 129);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dOrn-dNle-dVal-dPro-NH2 (SEQ ID NO: 130);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dSer-dVal-dPro-NH2 (SEQ ID NO: 131 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dPhe-dVal-dPro-NH2(SEQ ID NO: 132);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dOrn-dVal-dPro-NH2 (SEQ ID NO: 133);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dAsp-dVal-dPro-NH2 (SEQ ID NO: 134);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAsp-dNle-dVal-dPro-NH2 (SEQ ID NO: 135);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dSer-dVal-dPro-NH2 (SEQ ID NO: 136);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dPhe-dVal-dPro-NH2 (SEQ ID NO: 137);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dOrn-dVal-dPro-NH2 (SEQ ID NO: 138);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dAsp-dVal-dPro-NH2 (SEQ ID NO: 139); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dNle-dNle-dVal-dPro-NH2 (SEQ ID NO: 140), wherein c represents cyclization through R2and R7via a lactam bond.

49. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 10, 13-18, and 43, wherein Y2is selected from the group consisting of Phg, dPhg, Asp, and Orn.

50. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 10, 13-18, 43, and 49, wherein Y1is dAla or Gly.SMRH:4906-9094-6395 -181 -Docket No.: 183B-412969-WO51. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 10, 13-18, 43, 49, and 50, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-Phg-dVal-dPro-NH2(SEQ ID NO: 108); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhg-dVal-dPro-NH2(SEQ ID NO: 109); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Phg-dVal-dPro-NH2(SEQ ID NO: 1 10); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-dPhg-dVal-dPro-NH2(SEQ ID NO: 111 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-Asp-dVal-dPro-NH2(SEQ ID NO: 112); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Asp-dVal-dPro-NH2(SEQ ID NO: 1 13); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-Orn-dVal-dPro-NH2(SEQ ID NO: 114); and Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Orn-dVal-dPro-NH2(SEQ ID NO: 115), wherein c represents cyclization through R2and R7via a lactam bond.

52. The non-naturally occurring melanocortin analog of any one of claims 1 -4 and 13-18, wherein:Y4is dVal; andY5is dPro.

53. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 13-18, and 52, wherein Y1is dAla or Gly.

54. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 9, 13-18, 52, and 53, wherein Y3is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

55. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 9, 13-18, and 52-54, wherein Y2is dAla and Gly.

56. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 9, 13-18, and 52-55, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of:SMRH:4906-9094-6395 -182-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dSer-dVal-dPro-NH2 (SEQ ID NO:141 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dPhe-dVal-dPro-NH2(SEQ ID NO:142);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dOrn-dVal-dPro-NH2 (SEQ ID NO:143);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dAsp-dVal-dPro-NH2 (SEQ ID NO:144);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dNle-dVal-dPro-NH2 (SEQ ID NO:145);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dSer-dVal-dPro-NH2 (SEQ ID NO: 146); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dPhe-dVal-dPro-NH2 (SEQ ID NO: 147); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dOrn-dVal-dPro-NH2 (SEQ ID NO: 148); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dAsp-dVal-dPro-NH2 (SEQ ID NO: 149); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dNle-dVal-dPro-NH2 (SEQ ID NO: 150), wherein c represents cyclization through R2and R7via a lactam bond.

57. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 9, 13-18, and 52-54, wherein Y2is selected from the group consisting of dSer, dPhe, dOrn, dAsp, and dNIe.

58. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 9, 13-18, 52-54, and 57, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dSer-dVal-dPro-NH2(SEQ ID NO:159);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dPhe-dVal-dPro-NH2(SEQ ID NO:160);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dOrn-dVal-dPro-NH2 (SEQ ID NO:161 );SMRH:4906-9094-6395 -183-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dAsp-dVal-dPro-NH2(SEQ ID NO:162);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dSer-dNle-dVal-dPro-NH2(SEQ ID NO:163);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dSer-dVal-dPro-NH2(SEQ ID NO:164);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dPhe-dVal-dPro-NH2(SEQ ID NO:165);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dOrn-dVal-dPro-NH2(SEQ ID NO:166);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dAsp-dVal-dPro-NH2(SEQ ID NO:167);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dPhe-dNle-dVal-dPro-NH2(SEQ ID NO:168);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dSer-dVal-dPro-NH2(SEQ ID NO:169);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dPhe-dVal-dPro-NH2(SEQ ID NO:1 0);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dOrn-dVal-dPro-NH2(SEQ ID NO:171 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dAsp-dVal-dPro-NH2(SEQ ID NO:172);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dOrn-dNle-dVal-dPro-NH2(SEQ ID NO:173);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dSer-dVal-dPro-NH2(SEQ ID NO:174);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dPhe-dVal-dPro-NH2(SEQ ID NO:175);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dOrn-dVal-dPro-NH2(SEQ ID NO:176);SMRH:4906-9094-6395 -184-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dAsp-dVal-dPro-NH2(SEQ ID NO:177);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAsp-dNle-dVal-dPro-NH2(SEQ ID NO:178);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dSer-dVal-dPro-NH2(SEQ ID NO:179);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dPhe-dVal-dPro-NH2(SEQ ID NO:180);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dOrn-dVal-dPro-NH2(SEQ ID NO:181 );Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dAsp-dVal-dPro-NH2(SEQ ID NO:182); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dNle-dNle-dVal-dPro-NH2(SEQ ID NO:183), wherein c represents cyclization through R2and R7via a lactam bond.

59. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 10, 13-18, 52, and 53, wherein Y3is selected from the group consisting of Phg, dPhg, Asp, and Orn.

60. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 10, 13-18, 52, 53, and 59, wherein Y2is dAla and Gly.

61. The non-naturally occurring melanocortin analog of any one of claims 1 -4, 8, 10, 13-18, 52, 53, 59, and 60, wherein the sequence of any one of Formulae (l)-(IA(ii)) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-Phg-dVal-dPro-NH2(SEQ ID NO: 151 ); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-dPhg-dVal-dPro-NH2(SEQ ID NO: 152);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-Phg-dVal-dPro-NH2(SEQ ID NO: 153); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-dPhg-dVal-dPro-NH2(SEQ ID NO: 154);SMRH:4906-9094-6395 -185-Docket No.: 183B-412969-WOAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-Asp-dVal-dPro-NH2 (SEQ ID NO: 155); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-Asp-dVal-dPro-NH2(SEQ ID NO: 156);Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dAla-dAla-Orn-dVal-dPro-NH2 (SEQ ID NO: 157); andAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-Gly-Gly-Orn-dVal-dPro-NH2 (SEQ ID NO: 158), wherein c represents cyclization through R2and R7via a lactam bond.

62. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, and 1 1 -22, wherein the sequence of Formula (I) or (IB) is cyclized via a lactam bond between Orn at R2and Glu at R7.

63. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, 11 - 22, and 68, wherein the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dOrn-dVal-dPro-NH2(SEQ ID NO: 230);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dAla-dOrn-dVal-dPro-NH2 (SEQ ID NO: 231 ); Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 232);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 233);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 234); Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-dOrn-NH2 (SEQ ID NO: 235);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 236); Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 237);Ac-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 238); andAc-Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 239), wherein c represents cyclization through R2and R7via a lactam bond.

64. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, and 1 1 -22, wherein the sequence of Formula (I) or (IB) is cyclized via a lactam bond between Asp at R2and Lys at R7.SMRH:4906-9094-6395 -186-Docket No.: 183B-412969-WO65. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, 11 - 22, and 70, wherein R4is p(F)dPhe.

66. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, 11 - 22, 64, and 65, wherein the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dOrn-dVal-dPro-NH2(SEQ ID NO: 200); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 201 ); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 202);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 203);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 204); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-dOrn-NH2(SEQ ID NO: 205);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 206); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 207);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 208); andAc-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 209), wherein c represents cyclization through R2and R7via a lactam bond.

67. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, 11 - 22, and 64, wherein R4is dPhe.

68. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, 11 - 22, 64, and 67, wherein the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAsp-dVal-dPro-NH2(SEQ ID NO: 196); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dOrn-dVal-dPro-NH2(SEQ ID NO: 197); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 198); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 199);SMRH:4906-9094-6395 -187-Docket No.: 183B-412969-WOAc-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 250);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 251 );Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 252);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 253);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 254);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 255);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dAsp-NH2(SEQ ID NO: 256);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dOrn-NH2(SEQ ID NO: 257);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dAsp-NH2(SEQ ID NO: 258);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 259);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-dAsp-NH2(SEQ ID NO: 260); and Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 261 ); wherein c represents cyclization through R2and R7via a lactam bond.

69. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, and 1 1 -22, wherein the sequence of Formula (I) or (IB) is cyclized via a lactam bond between Lys at R2and Asp at R7.

70. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, 11 - 22, and 69, wherein R4is p(F)dPhe.71 . The non-naturally occurring melanocortin analog of any one of claims 1 , 2, 11 - 22, 69, and 70, wherein the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dOrn-dVal-dPro-NH2(SEQ ID NO: 220);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 221 );Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 222);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 223);Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 224); Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-dOrn-NH2(SEQ ID NO: 225);SMRH:4906-9094-6395 -188-Docket No.: 183B-412969-WOAc-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 226); Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 227); Ac-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 228); andAc-Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 229), wherein c represents cyclization through R2and R7via a lactam bond.

72. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, 11 - 22, and 69, wherein R4is dPhe.

73. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, 11 - 22, 69, and 72, wherein the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAsp-dVal-dPro-NH2(SEQ ID NO: 262); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dOrn-dVal-dPro-NH2(SEQ ID NO: 263); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 264);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 265); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 266); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 267);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dAla-dAsp-dVal-dPro-NH2(SEQ ID NO: 268); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 269); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-Gly-dAsp-dVal-dPro-NH2(SEQ ID NO: 270);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 271 ); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dAsp-NH2(SEQ ID NO: 272);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dOrn-NH2(SEQ ID NO: 273); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dAsp-NH2(SEQ ID NO: 274); Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 275);Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-dAsp-NH2(SEQ ID NO: 276); and Ac-Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 277), wherein c represents cyclization through R2and R7via a lactam bond.SMRH:4906-9094-6395 -189-Docket No.: 183B-412969-WO74. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, and 1 1 -22, wherein the sequence of Formula (I) or (IB) is cyclized via a lactam bond between Aad at R2and Dab at R7.

75. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, 11 - 22, and 74, wherein the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dOrn-dVal-dPro-NH2(SEQ ID NO: 210); Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 211 ); Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 212);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 213);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 214); Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-dOrn-NH2(SEQ ID NO: 215);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 216); Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 217);Ac-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 218); andAc-Nle-c[Aad-His-p(F)dPhe-Arg-Trp-Dab]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 219), wherein c represents cyclization through R2and R7via a lactam bond.

76. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, and 1 1 -22, wherein the sequence of Formula (I) or (IB) is cyclized via a lactam bond between Dab at R2and Aad at R7.

77. The non-naturally occurring melanocortin analog of any one of claims 1 , 2, 11 - 22, and 76, wherein the sequence of Formula (I) or (IB) is selected from the group consisting of:Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dOrn-dVal-dPro-NH2(SEQ ID NO: 240); Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 241 ); Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 242);SMRH:4906-9094-6395 -190-Docket No.: 183B-412969-WOAc-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dAla-dAla-dOrn-dVal-dPro-NH2(SEQ ID NO: 243);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-Gly-Gly-dOrn-dVal-dPro-NH2(SEQ ID NO: 244);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-dOrn-NH2(SEQ ID NO: 245);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-dAla-dOrn-NH2(SEQ ID NO: 246);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-Gly-dOrn-NH2(SEQ ID NO: 247);Ac-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-dAla-dAla-dOrn-NH2(SEQ ID NO: 248); andAc-Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Aad]-dVal-dPro-Gly-Gly-dOrn-NH2(SEQ ID NO: 249), wherein c represents cyclization through R2and R7via a lactam bond.

78. The non-naturally occurring melanocortin analog of any one of claims 1 -77, wherein the non-naturally occurring melanocortin analog is present in a pharmaceutical composition.

79. The non-naturally occurring melanocortin analog of claim 78, wherein the pharmaceutical composition further comprises a pharmaceutical salt.

80. The non-naturally occurring melanocortin analog of claim 78, wherein the pharmaceutical composition further comprises a pharmaceutical carrier.

81. The non-naturally occurring melanocortin analog of claim 80, wherein the pharmaceutical carrier comprises water.

82. The non-naturally occurring melanocortin analog of claim 78, 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.

83. The non-naturally occurring melanocortin analog of claim 78, 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.SMRH:4906-9094-6395 -191 -Docket No.: 183B-412969-WO84. The non-naturally occurring melanocortin analog of claim 78, 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.

85. The non-naturally occurring melanocortin analog of any one of claims 1 -84, wherein the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

86. The non-naturally occurring melanocortin analog of any one of claims 78-85, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally.

87. The non-naturally occurring melanocortin analog of any one of claims 78-86, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.

88. The non-naturally occurring melanocortin analog of any one of claims 1 -87, wherein the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of the subject.

89. The non-naturally occurring melanocortin analog of any one of claims 1 -88, 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.

90. The non-naturally occurring melanocortin analog of any one of claims 1 -89, 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.SMRH:4906-9094-6395 -192-Docket No.: 183B-412969-WO91. The non-naturally occurring melanocortin analog of any one of claims 1 -90, 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.

92. The non-naturally occurring melanocortin analog of any one of claims 1 -91 , 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.

93. The non-naturally occurring melanocortin analog of any one of claims 1 -92, 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.

94. The non-naturally occurring melanocortin analog of any one of claims 1 -98, 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.SMRH:4906-9094-6395 -193-

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