ABSTRACT
Title
Evolution in structure/activity relationship of melanocortin receptor agonists and antagonists: a new class of drugs with a multifaceted therapeutic profile
Authors
P. Grieco, A. Carotenuto, L. Auriemma, S. Di Maro, E. Novellino
Dip. Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II
Via D. Montesano, 49 80131 Napoli, ITALY
Dip. Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II
Via D. Montesano, 49 80131 Napoli, ITALY
Abstract
The melanocortin system is important for a diverse number of physiological roles and pathways. Extensive structure-activity relationships have been established that all the melanocortin ligands contain the important “core” sequence His-Phe-Arg-Trp. It has been proposed (J. Med.Chem. 1995, 38, 3454) that this tetrapeptide core sequence is a key component for molecular recognition and melanocortin receptor activation. We report here structural modifications of the lead agonist, MTII, Ac-Nle-c[Asp-His-DPhe-Arg-Trp]-Lys-NH2, and the lead antagonist SHU9119, Ac-Nle-c[Asp-His-DNla(2)-Arg-Trp]-Lys-NH2. The results were performed and evaluated on human melanocortin receptors.
In particular, modifications of the MTII and SHU9119 templates by incorporation of constrained amino acids in core sequence of these important peptides, resulted in significant change of bioactivity in potency and receptor selectivity when compared with their respective “parent” template. This study allowed us to discover a series of analogues which are highly potent and selective agonists and/or antagonists at the hMC3, hMC4, and hMC5 receptors. In order to understand which “bioactive conformation” is the most important and specific to interact selectively at hMC3 and hMC4, we carried out a molecular modeling study. Here, we will propose a 3D pharmacophore model for the ligands of hMC3 and hMC4 receptors obtained by molecular modeling which employed low-energy conformations of peptides possessing a pronounced hMC3 and hMC4 selectivity. This model is well supported by synthesis and biological testing of several conformationally constrained cyclic peptides.
In particular, modifications of the MTII and SHU9119 templates by incorporation of constrained amino acids in core sequence of these important peptides, resulted in significant change of bioactivity in potency and receptor selectivity when compared with their respective “parent” template. This study allowed us to discover a series of analogues which are highly potent and selective agonists and/or antagonists at the hMC3, hMC4, and hMC5 receptors. In order to understand which “bioactive conformation” is the most important and specific to interact selectively at hMC3 and hMC4, we carried out a molecular modeling study. Here, we will propose a 3D pharmacophore model for the ligands of hMC3 and hMC4 receptors obtained by molecular modeling which employed low-energy conformations of peptides possessing a pronounced hMC3 and hMC4 selectivity. This model is well supported by synthesis and biological testing of several conformationally constrained cyclic peptides.