Article April 28, 2017
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Cite this: J. Med. Chem. 2017, 60, 10
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Published April 28, 2017
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Copyright © 2017 American Chemical Society
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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.
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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b00301.
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