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 Article

Doering, SR, Freeman, KT, Schnell, SM et al. (2017). 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 . JOURNAL OF MEDICINAL CHEMISTRY, 60(10), 4342-4357. 10.1021/acs.jmedchem.7b00301

cited authors

  • Doering, SR; Freeman, KT; Schnell, SM; Haslach, EM; Dirain, M; Debevec, G; Geer, P; Santos, RG; Giulianotti, MA; Pinilla, C; Appel, JR; Speth, RC; Houghten, RA; Haskell-Luevano, C

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-NH2], 1 [Ac-His-Arg-(pI)DPhe-Tic-NH2], and 41 [Ac-Arg-Arg-(pI)DPhe-DNal(2′)-NH2] were more potent (EC50 < 73 nM) than the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH2. 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.

publication date

  • May 25, 2017

published in

Digital Object Identifier (DOI)

start page

  • 4342

end page

  • 4357

volume

  • 60

issue

  • 10