Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa 1 -Arg-(pI)DPhe-Xaa 4 -NH 2 .

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-Xaa ¹ -Arg-(pI)DPhe-Xaa ⁴ -NH ₂ ] 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 (EC ₅₀ < 1000 nM) and MC4R antagonists (5.7 < pA ₂ < 7.8). The three most potent MC3R agonists, 18 [Ac-Arg-Arg-(pI)DPhe-Tic-NH ₂ ], 1 [Ac-His-Arg-(pI)DPhe-Tic-NH ₂ ], and 41 [Ac-Arg-Arg-(pI)DPhe-DNal(2')-NH ₂ ] were more potent (EC ₅₀ < 73 nM) than the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH ₂ . This template contains a sequentially reversed "Arg-(pI)DPhe" motif with respect to the classical "Phe-Arg" melanocortin signaling motif, which results in pharmacology that is first-in-class for the central melanocortin receptors.