Novel agouti-related-protein-based melanocortin-1 receptor antagonist
Novel agouti-related-protein-based melanocortin-1 receptor antagonist
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DOI：
10.1021/jm010215z
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发表时间：
2001-11-22
影响因子：
7.3
通讯作者：
Haskell-Luevano, C
中科院分区：
文献类型：
--
作者：
Thirumoorthy, R;Holder, JR;Haskell-Luevano, C
黑皮质素受体是G蛋白偶联受体（GPCR），其激活cAMP信号转导途径并由黑皮质素激动剂α-黑素细胞刺激激素（α-MSH）刺激。这些黑皮质素受体的成员被agonists（ASP）和agouti-related protein（AGRP）拮抗，它们是迄今为止唯一已知的GPCR的内源性拮抗剂。通过对hAGRP（109-118）十肽Tyr-c[Cys-Arg-Phe-Phe-Asn-Ala-Phe-Cys]-Tyr-NH 2的结构-功能研究，通过用内酰胺桥取代26元二硫键Cys（2）-Cys（9）环，鉴定了一种新的外周皮肤黑皮质素-1受体（MC 1 R）拮抗剂。该拮抗剂Tyr-c[Glu-Arg-Phe-Phe-Asn-Ala-Phe-Dpr]-Tyr-NH 2具有27元环，内酰胺桥由Glu的Ca-羧基部分（而不是典型的侧链羧基部分）与二氨基丙酸（Dpr）残基的胺形成。这种小鼠MC 1受体拮抗剂（pA（2）= 5.9）也是脑黑皮质素-4受体（pA（2）= 6.9）的拮抗剂，对黑皮质素-3或-5受体没有可观察到的药理学作用。这种基于MC 1 R hAGRP（109-118）的十肽是新颖的，因为AGRP（83-132）本身不结合、激动或拮抗皮肤MC 1 R。使用二维H-1 NMR和计算机辅助分子建模（CAMM）技术进行了结构分析，试图鉴定该Tyr-c[Glu-Arg-Phe-Phe-Asn-Ala-Phe-Dpr]-Tyr-NH 2（环Glu α COOH-Dpr β NH）肽的结构特征，这些结构特征可在mMC 1 R处产生不同的拮抗剂与激动剂特性。
The melanocortin receptors are G-protein coupled receptors (GPCRs) that activate the cAMP signal transduction pathway and are stimulated by the melanocortin agonist a-melanocyte stimulating hormone (a-MSH). Members of these melanocortin receptors are antagonized by agouti (ASP) and agouti-related protein (AGRP), which are the only known endogenous antagonists 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-membered disulfide Cys(2)-Cys(9) ring with lactam bridges resulted in the identification of a novel peripheral skin 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 formed from the Ca-carboxyl moiety of Glu (instead of the typical side chain carboxyl moiety) with the amine of the diaminopropionic acid (Dpr) residue. This mouse MC1 receptor antagonist (pA(2) = 5.9) is also an antagonist at the brain melanocortin-4 receptor (pA(2) = 6.9), with no observable 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 antagonize the skin MC1R. Structural analysis has been performed using two-dimensional H-1 NMR and computer-assisted molecular modeling (CAMM) techniques in attempts to identify structural features of this Tyr-c[Glu-Arg-Phe-Phe-Asn-Ala-Phe-Dpr]-Tyr-NH2 (cyclo Glu alpha COOH-Dpr beta NH) peptide that can differentially result in antagonist versus agonist properties at the mMC1R.