Structure–activity studies of new melanocortin peptides containing an aromatic amino acid at the N-terminal position

Cyclic melanotropin peptides, designed with an aromatic amino acid substitution at the N-terminal position of the MT-II-type scaffold, were prepared by solid-phase peptide synthesis and evaluated for their ability to bind to and activate human melanocortin-1, -3, -4, and -5 receptors. The structure–activity studies of these MT-II analogues have identified a selective antagonist at the hMC4R (H-Phe-c[Asp-Pro-d-Nal(2′)-Arg-Trp-Gly-Lys]-NH2, pA2 = 8.7), a selective partial agonist at the hMC4R (H-d-Nal(2′)-c[Asp-Pro-d-Phe-Arg-Trp-Gly-Lys]-NH2, IC50 = 11 nM, EC50 = 56 nM), and a selective partial agonist at the hMC3R (H-d-Phe-c[Asp-Pro-d-Phe-Arg-Trp-Lys]-NH2, IC50 = 3.7 nM, EC50 = 4.9 nM). Aromatic amino acid substitution at the N-terminus in conjuction with the expansion of the 23-membered cyclic lactam MT-II scaffold to a 26-membered scaffold by addition of a Gly residue in position 10 leads to melanotropin peptides with enhanced receptor selectivity.