Novel Macrocyclic Peptides Active at Human Melanocortin Receptors: A Preliminary SAR Study

摘要

The melanocortins are a group of structurally related peptides derived from proopiomelanocortin (POMC), their name from their melanotropic and corticotropic activities and are comprised of adrenocorticotropic hormone (ACTH), a-melanocyte stimulating hormone (α-MSH), β-MSH, and γ-MSH. The effects of melanocortins are mediated by activation of a family of melanocortin receptors (MCRs). Five MCR (MC1R, MC2R, MC3R, MC4R, and MC5R) (Figure 2) genes have been cloned and the receptors pharmacologically characterized [1]. All the melanocortin ligands conserve the core sequence, Trp-Arg-Phe-His. Previous SAR study on melanotropins, in particular on a-MSH, led to the small cyclic peptide MT-II, a potent and non-selective agonist at MCRs. Similarly, the lactam analogue, SHU-9119, is an antagonist at MCRs 3 and 4 receptors. Subsequently, we developed a series of novel 20-membered macrocycles formally derived from MTII and SHU9119, containing an alkylthioaryl bridge. Based on these considerations, herein we synthesized a new cyclic lactam peptide analogues of a-MSH containing α,α-disubstituted amino acids to provide further SAR study.