Modulators of melanocortin receptors (MCR) are provided herein. An MC5R peptide ligand is represented by to Formula 1:
R.sub.1-Nle.sup.4-c[Xaa.sup.5-Yaa.sup.6-(NMe)D-Nal(2′).sup.7-Arg.sup.8-Trp.sup.9-(NMe)Zaa.sup.10]-R.sub.2.
R.sub.1 can be an acetyl, a glycosylated amino acid, —CO—(CH.sub.2).sub.nCH.sub.3, or —CO—(CH.sub.2).sub.nCF.sub.3 with n ranging from 1 to 6. R.sub.2 can be an —CONH.sub.2, —COOH, or —CH.sub.2OH. Xaa, Yaa, and Zaa can each be a natural amino acid or an unnatural amino acid.

The disclosure is related to a method of treating a disorder, such as Prader Willi Syndrome (PWS), obesity or hyperphagia, in a subject using a melanocortin-4 receptor (MC4R) agonist. Also described is method of treating a subject having a deficiency in the pro-opiomelanocortin (POMC)-MC4R pathway, such as a POMC-null or a PC SK-null subject, using a MC4R agonist.

The disclosure is related to a method of treating a disorder, such as Prader Willi Syndrome (PWS), obesity or hyperphagia, in a subject using a melanocortin-4 receptor (MC4R) agonist. Also described is method of treating a subject having a deficiency in the pro-opiomelanocortin (POMC)-MC4R pathway, such as a POMC-null or a PC SK-null subject, using a MC4R agonist.

The present invention relates to polypeptide compounds that are modulators (e.g., agonists and antagonists) of the melanocortin-4 receptor (MC4R) and pharmaceutical compositions comprising same. The compounds described herein are polypeptide of the following structural Formula (I):

##STR00001##

or a pharmaceutically acceptable salt thereof. Values and preferred values of the variables in structural Formula (I) are described herein.

The present invention relates to polypeptide compounds that are modulators (e.g., agonists and antagonists) of the melanocortin-4 receptor (MC4R) and pharmaceutical compositions comprising same. The compounds described herein are polypeptide of the following structural Formula (I):

##STR00001##

or a pharmaceutically acceptable salt thereof. Values and preferred values of the variables in structural Formula (I) are described herein.

The disclosure is related to a method of treating a disorder, such as Prader Willi Syndrome (PWS), obesity or hyperphagia, in a subject using a melanocortin-4 receptor (MC4R) agonist. Also described is method of treating a subject having a deficiency in the pro-opiomelanocortin (POMC)-MC4R pathway, such as a POMC-null or a PCSK-null subject, using a MC4R agonist.

The disclosure is related to a method of treating a disorder, such as Prader Willi Syndrome (PWS), obesity or hyperphagia, in a subject using a melanocortin-4 receptor (MC4R) agonist. Also described is method of treating a subject having a deficiency in the pro-opiomelanocortin (POMC)-MC4R pathway, such as a POMC-null or a PCSK-null subject, using a MC4R agonist.

The invention described herein is based in part on the discovery of a protein/peptide crosslink, which introduces fluorescent properties, and which has been applied to synthesize analogues of melanocortin and amanitin as choice peptides to be explored in the context of isoindole peptides. Without limitation, it is expected that those trained in the art of peptide synthesis and stapling would appreciate the consequences of this invention such that other peptides of varied length can be similarly constrained by isoindole staples as featured herein.

The invention described herein is based in part on the discovery of a protein/peptide crosslink, which introduces fluorescent properties, and which has been applied to synthesize analogues of melanocortin and amanitin as choice peptides to be explored in the context of isoindole peptides. Without limitation, it is expected that those trained in the art of peptide synthesis and stapling would appreciate the consequences of this invention such that other peptides of varied length can be similarly constrained by isoindole staples as featured herein.

The present invention relates to polypeptide compounds that are modulators (e.g., agonists and antagonists) of the melanocortin-4 receptor (MC4R) and pharmaceutical compositions comprising same. The compounds described herein are polypeptide of the following structural Formula (I): ##STR00001##
or a pharmaceutically acceptable salt thereof. Values and preferred values of the variables in structural Formula (I) are described herein.