Analogs of MTII, lactam derivatives of α-melanotropin, modified at the N-terminus, and their selectivity at human melanocortin receptors 3, 4, and 5

In search for selective agonists at human melanocortin-4 receptor, proline-substituted analogs of MTII, a potent nonselective agonist at melanocortin receptors, were prepared by solid-phase syntheses and evaluated for their ability to bind and activate human MC-3, MC-4, and NIC-B receptors. Replacement of Nle(4) with Pro resulted in [Pro(4)]MTII with affinity to and agonist potency at hMC-4R similar to MTII, but with about 400-fold lower potency at hMC-5R and about 20-fold lower potency at hMC-3R. The substantial increase in selectivity of [Pro(4)]MTII with respect to hMC-5R prompted us to investigate additional analogs of MTII with modified N-termini. The Ac-Nle(4) segment, not encompassed in the lactam ring, was substituted with flexible, hydrophobic, or hydrophilic substituents, and also, with residues resembling proline. The similar agonist potency of these peptides to that of MTII at hMC-4R but significantly lower activity of these compounds at hMC-5R demonstrated that the N-terminal fragment of MTII has virtually no effect on the binding affinity and activation at hMC-4R, but it is essential for full potency at hMC-BR. (C) 1999 Academic Press.