Analogs for CLR/RAMP receptor ligands are provided that have agonist, superagonist, antagonist, super-antagonist, or multiple receptor modulatng activity. The analogs can be selective for one or more CLR/RAMP receptors, or can be pan-specific for multiple G protein-coupled receptors.

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.

Analogs for CLR/RAMP receptor ligands are provided that have agonist, superagonist, antagonist, super-antagonist, or multiple receptor modulating activity. The analogs can be selective for one or more CLR/RAMP receptors, or can be pan-specific for multiple G protein-coupled receptors.

Methods preventing, ameliorating or treating cytokine storm or inflammatory disease, indications, conditions and syndromes by administration of a therapeutically effective amount of a melanocortin-1 receptor-specific cyclic peptide or pharmaceutically acceptable salt thereof.

Methods preventing, ameliorating or treating cytokine storm or inflammatory disease, indications, conditions and syndromes by administration of a therapeutically effective amount of a melanocortin-1 receptor-specific cyclic peptide or pharmaceutically acceptable salt thereof.

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.

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 present invention relates to novel peptide compounds which are effective as melanocortin 4 receptor agonists, to the use of the compounds in medicine, to methods of treatment comprising administration of the compounds to patients in need thereof, and to the use of the compounds for the manufacture of medicaments. The compounds of the invention are of particular interest in relation to the treatment of overweight and obesity as well as a variety of diseases or conditions associated with obesity.

The present invention relates to novel peptide compounds which are effective as melanocortin 4 receptor agonists, to the use of the compounds in medicine, to methods of treatment comprising administration of the compounds to patients in need thereof, and to the use of the compounds for the manufacture of medicaments. The compounds of the invention are of particular interest in relation to the treatment of overweight and obesity as well as a variety of diseases or conditions associated with obesity.

The present invention relates to peptide ligands of the melanocortin receptors, in particular the melancortin-4 receptor, and as such, are useful in the treatment of disorders responsive to the activation of this receptor, such as obesity, diabetes mellitus and sexual dysfunction.