| Abstract
| - The melanocortin receptors are G-protein coupled receptors (GPCRs) that activate the cAMPsignal transduction pathway and are stimulated by the melanocortin agonist α-melanocytestimulating hormone (α-MSH). Members of these melanocortin receptors are antagonized byagouti (ASP) and agouti-related protein (AGRP), which are the only known endogenousantagonists of GPCRs identified to date. Structure−function studies of the hAGRP(109−118)decapeptide, Tyr-c[Cys-Arg-Phe-Phe-Asn-Ala-Phe-Cys]-Tyr-NH2, by replacing the 26-membereddisulfide Cys2-Cys9 ring with lactam bridges resulted in the identification of a novel peripheralskin melanocortin-1 receptor (MC1R) antagonist. This antagonist, Tyr-c[Glu-Arg-Phe-Phe-Asn-Ala-Phe-Dpr]-Tyr-NH2, possesses a 27-membered ring with the lactam bridge being formedfrom the Cα-carboxyl moiety of Glu (instead of the typical side chain carboxyl moiety) with theamine of the diaminopropionic acid (Dpr) residue. This mouse MC1 receptor antagonist(pA2 = 5.9) is also an antagonist at the brain melanocortin-4 receptor (pA2 = 6.9), with noobservable pharmacology at the melanocortin-3 or -5 receptors. This MC1R hAGRP(109−118)based decapeptide is novel in that AGRP(83−132) itself does not bind to, agonize, or antagonizethe skin MC1R. Structural analysis has been performed using two-dimensional 1H NMR andcomputer-assisted molecular modeling (CAMM) techniques in attempts to identify structuralfeatures of this Tyr-c[Glu-Arg-Phe-Phe-Asn-Ala-Phe-Dpr]-Tyr-NH2 (cyclo Glu αCOOH-Dpr βNH)peptide that can differentially result in antagonist versus agonist properties at the mMC1R.
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