Tetrapeptide Melanocortin Agonist Ligands Exploring Selectivity of the mMC3R Using DPhe Substitutions in the Ac-His-Arg-DPhe-Tic-NH2 Scaffold

Abstract

There are five melanocortin receptors (MC1R-MC5R) that primarily activate the signaling pathway for adenylate cyclase. While both the MC3R and MC4R are hypothesized to be involved in regulating energy homeostasis, the MC3R functionality has been elusive to characterize due to the lack of MC3R-selective ligands. The melanocortin system may be a target for treating obesity or cachexia. When centrally delivered through intracerebroventricular administration, agonists decrease food intake, while antagonists increase food intake. Previous weight management therapies have focused on targeting the MC4R, though off-target cardiovascular effects may limit the clinical utility of these ligands. Therefore, obtaining a MC3R selective compound may allow for a weight regulation therapy that will not have the same cardiovascular liabilities. MC4R-selective ligands have been heavily investigated, however MC3R-selective ligands have largely gone unexplored. A mixture-based positional scan was conducted to generate scaffolds with MC3R selectivity. The lead compound from the study was Ac-His-Arg-(pI)DPhe-Tic-NH2, an MC3R agonist and an MC4R antagonist. The scaffold reverses the sequence of arginine and phenylalanine residues in the His-Phe-Arg-Trp conserved sequence found in endogenous melanocortin ligands1. This work presents a follow-up study investigating the position of the phenylalanine residue in efforts to create a MC3R selective agonist with decreased MC4R antagonist activity.