Study of Novel Designed Human MC4R Selective Ligands

Abstract

G-protein coupled receptors (GPCRs) are the target of a large number of drugs. Among them, melanocortin receptors (MCRs) are the most exciting receptors to study due to melanocortin system is a primordial system which is critical for survival. Within 5 subtypes melanocortin receptor that controls different physiological functions, melanocortin 4 receptor plays an important role for the feeding behavior and sexual behavior. My research focused on developing selective MC4R agonists. By keeping the (D)Phe-Arg-Trp core sequence, changing Arg/Trp to either beta-homo-Trp/beta-homo-Arg or both, replacing His to Pip and Nle to Arg, applying the para fluorine and para chlorine strategy in our designed series, we discovered that AIM9 in the series was the selective MC4R agonist. Plasmon waveguided resonance (PWR) spectroscopy studies reveal that the conformational changes in agonist and antagonist induced receptors could be detected.