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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2017 Apr 29

PMID 28453292

Citations 12

Authors

Skye R Doering

Katie T Freeman

Sathya M Schnell

Erica M Haslach

Marvin Dirain

Ginamarie Debevec

Phaedra Geer

Radleigh G Santos

Marc A Giulianotti

Clemencia Pinilla

Jon R Appel

Robert C Speth

Richard A Houghten

Carrie Haskell-Luevano

Affiliations

Soon will be listed here.

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-Xaa-Arg-(pI)DPhe-Xaa-NH] 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 < 1000 nM) and MC4R antagonists (5.7 < pA < 7.8). The three most potent MC3R agonists, 18 [Ac-Arg-Arg-(pI)DPhe-Tic-NH], 1 [Ac-His-Arg-(pI)DPhe-Tic-NH], and 41 [Ac-Arg-Arg-(pI)DPhe-DNal(2')-NH] were more potent (EC < 73 nM) than the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH. 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.

Citing Articles

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