Discovery of Polypharmacological Melanocortin-3 and −4 Receptor Probes and Identification of a 100-Fold Selective nM MC3R Agonist versus a µM MC4R Partial Agonist

The centrally expressed melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are established targets to treat diseases of positive and negative energy homeostasis. We previously reported (J. Med. Chem. 60:4342 2017) mixture-based positional scanning approaches to identify dual MC3R agonist and MC4R antagonist tetrapeptides. Herein, 46 tetrapeptides were chosen for MC3R agonist screening selectivity profiles, synthesized, and pharmacologically characterized at the mouse melanocortin-1, −3, −4, and −5 receptors. Substitutions to the tetrapeptide template were selected solely based on MC3R agonist potency from the mixture-based screen. This study resulted in the discovery of compound 42 (Ac-Val-Gln-(pI)DPhe-DTic-NH 2 ), a full MC3R agonist that is 100-fold selective for the MC3R over the µM MC4R partial agonist pharmacology. This compound represents a first-in-class MC3R-selective agonist. This ligand will serve as a useful in vivo molecular probe for the investigation of the roles of the MC3R and MC4R in diseases of dysregulated energy homeostasis.