Highly Selective Cyclic Peptides for Human Melanocortin-4 Receptor (MC-4 R): Design, Synthesis, Bioactive Conformation, and Pharmacological Evaluation as an Anti-Obesity Agent

Abstract

Melanocortin (MC) peptides α-, β-, and γ-MSH and adreno-corticotropic hormone (ACTH) are a group of neuropeptides derived from pro-opiomelanocortin hormone (POMC). The physiological actions of these peptides are mediated through five (MCR-1–5) seven-transmembrane G-protein-coupled receptor subtypes. The MSH peptides have been implicated in numerous biological functions [1] including regulation of skin pigmentation, regulation of steroid production, modulation of the immune response, thermo-regulation and obesity [2]. Clarification of the role of melanocortin receptor subtypes, in particular the recently discovered MC-3, MC-4 and MC-5 receptors, has been hampered by the lack of selective peptide ligands. However, recent studies on MCR knockout animals demonstrated that the MC-4 receptor is involved in regulation of feeding. MCR-4 knockout mice display an obesity phenotype that includes maturity onset obesity, hyperglycemia, and hyperinsulinemia. Moreover, it has been reported that a non-selective cyclic MCR-4 peptide agonist (MT II) inhibits food intake when given icv to mice [3]. Consequently, a potent and selective MC-4R agonist is regarded as potentially useful in therapeutic approaches to obesity management. The goal of this work was to identify a selective MCR-4 cyclic peptide agonist for use as a pharmacological tool in obesity and feeding studies and to develop a pharmacophore model applicable to structure-based drug design.