Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa¹-Arg-(pI)DPhe-Xaa⁴-NH₂.

ABSTRACT: The centrally expressed melanocortin-3 and -4 receptors (MC3R/MC4R) have been studied as possible targets for weight management therapies, with a preponderance of studies focusing on the MC4R. Herein, a novel tetrapeptide scaffold [Ac-Xaa¹-Arg-(pI)DPhe-Xaa⁴-NH₂] is reported. The scaffold was derived from results obtained from a MC3R mixture-based positional scanning campaign. From these results, a set of 48 tetrapeptides were designed and pharmacologically characterized at the mouse melanocortin-1, -3, -4, and -5 receptors. This resulted in the serendipitous discovery of nine compounds that were MC3R agonists (EC₅₀ < 1000 nM) and MC4R antagonists (5.7 < pA₂ < 7.8). The three most potent MC3R agonists, 18 [Ac-Arg-Arg-(pI)DPhe-Tic-NH

SUBMITTER: Doering SR 

PROVIDER: S-EPMC5672800 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature