Design Strategies to Produce Receptor Subtype Selective Peptide Agonists and Antagonists for Melanocortie Receptor System

摘要

The melanocortin receptor system consists of five different subtypes (MCIR, MC2R, MC3R, MC4R and MC5R) and all belong to the transmembrane G-protein coupled receptors (GPCRs) super family [1]. The peptide α-MSH is a nonselective endogenous agonist for these receptors except MC2R. The segment His-Phe-Arg-Trp of aMSH has been characterized as the essential pharmacophore for biological activity. Many different synthetic peptide analogues based on this tetrapeptide segment have been shown to be excellent agonists and antagonists for melanocortin receptors, but most of them have not shown receptor subtype selectivity. It remains a daunting challenge to produce a peptide antagonist with exclusive selectivity toward a particular subtype of melanocortin receptor [2]. A number of novel cyclic y-MSH analogues were designed and synthesized. One of these peptides MSG606 demonstrated potent antagonist activity and receptor selectivity for the hMClR (IC_(50) = 17 nM). In our continued effort to produce receptor subtype selective agonist/antagonist peptides, we have designed different series of peptides targeting the MC3R receptor. The synthesis of the peptides was successfully accomplished by using the standard solid-phase synthesis method. The peptides are currently being evaluated for their biological property.