Structure-Activity Relationships of alpha-MSH Analogues at the Human Melanocortin MC3, MC4, and MC5 Receptors. Discovery of Highly Selective hMC3R, hMC4R, and hMC5R Analogues.

It has been shown by extensive studies that melanotropin bioactivities are critically dependent on the core or central tetrapeptide sequence, His-Phe-Arg-Trp, and in R-MSH it has been demonstrated further that a reverse-turn type conformation exists at this pharmacophore. To probe the receptor active conformation of the pharmacophore His-Phe-Arg-Trp in ç-MSH, two different series of ç-MSH analogues have been designed and synthesized and their biological activities determined at hMC3R, hMC4R, and hMC5R. The 1st series consists of a cyclic scan using different disulfides or lactam bridges. It was found that cyclization of the native ç-MSH around the highly conserved sequence can lead to shifts in affinity and selectivity for hMC4R instead of the hMC3R as seen in the native peptide. Furthermore, a 23-membered ring is desirable for potency (e.g., analogues 6 and 10) whereas a 26-membered ring (analogue 1, H-Tyr- Val-c[Cys-Gly-His-Phe-Arg-Trp-Cys]-Arg-Phe-Gly-NH2 with Gly4) is more important for selectivity. The 2nd series is made of D-2-naphthylalanine (D-Nal(2¢)) scan of the ç-MSH sequence at position 6 and 8 and the replacement of His5 with Pro (analogue 13). Analogue 12, H-Tyr-Val- Nle-Gly-His-Phe-Arg-D-Nal(2¢)-Asp-Arg-Phe-Gly-NH2, is a potent and selective antagonist at the hMC4R, and analogue 15, H-Tyr-Val-Nle-Gly-Aib-Phe-Arg-D-Nal(2¢)-Asp-Arg-Phe-Gly-NH2, is a highly selective and potent agonist of the hMC5R. A most promising analogue is 13, H-Tyr- Val-Nle-Gly-Pro-D-Nal(2¢)-Arg-Trp-Asp-Arg-Phe-Gly-NH2, which is a very potent agonist of the hMC4R, and this analogue can be further evaluated for feeding behavior and the regulation of fat stores.