文摘
The physiological role of melanocortin receptor 5 (MC5R) in humans is not clear despite its broad presencein various peripheral sites and in the brain, cortex, and cerebellum. To differentiate between functions ofthis receptor and those of the other melanocortin receptors (hMC1,3,4R), peptides with improved receptorsubtype selectivity are needed. The endogenous ligands, melanocortins, and their various synthetic analoguesare 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 testedin binding and functional assays on CHO cells expressing hMC1b,3-5R. The analogues included in theirstructures 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 athMC5R. 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 nMand EC50 = 0.99 nM at hMC5R and selectivity for this receptor with respect to the other melanocortinreceptors greater than 5000-fold.
