Potent and Selective Agonists of Human Melanocortin Receptor 5:  Cyclic Analogues of α-Melanocyte-Stimulating Hormone

The physiological role of melanocortin receptor 5 (MC5R) in humans is not clear despite its broad presence in various peripheral sites and in the brain, cortex, and cerebellum. To differentiate between functions of this receptor and those of the other melanocortin receptors (hMC1,3,4R), peptides with improved receptor subtype selectivity are needed. The endogenous ligands, melanocortins, and their various synthetic analogues are not particularly selective for hMC5R. In this study, cyclic peptides derived from MTII, Ac-Nle-cyclo(Asp-His6-d-Phe7-Arg8-Trp-Lys)-NH2 (a pan-agonist at the melanocortin receptors) were prepared and tested in binding and functional assays on CHO cells expressing hMC1b,3−5R. The analogues included in their structures sterically constrained hydrophobic amino acids in positions 6 (His) and 8 (Arg), and the d-4,4‘-biphenyl residue in position 7 (d-Phe). Several of the new compounds were selective potent agonists at hMC5R. They are exemplified by peptide 29, Ac-Nle-cyclo(Asp-Oic6-d-4,4‘-Bip7-Pip8-Trp-Lys)-NH2 (Oic = octahydroindole-2-COOH; 4,4‘-Bip = 4,4‘-biphenylalanine; Pip = pipecolic acid) of IC50 = 0.95 nM and EC50 = 0.99 nM at hMC5R and selectivity for this receptor with respect to the other melanocortin receptors greater than 5000-fold.