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.
Bibliographical noteFunding Information:
We acknowledge Anamika Singh, Srinivasa Tala, Stacey Wilber, Mark Ericson, Katlyn Fleming, Cody Lensing, and Danielle Adank for their aid in the preparation of this manuscript. This work was supported in part by NIH R01 grant R01DK091906 (C.H.L.), and RO1DA031370 (R.A.H.), the State of Florida, Executive Office of the Governor?s Office of Tourism, Trade, and Economic Development (R.A.H.), and a Pilot Award from the Translational Technologies Component of the Georgetown, Howard Universities Center for Clinical and Translational Science, UL1TR000101 (R.C.S.), and NIH HL-113905 (R.C.S.)
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