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新型选择性人黑皮质素-3受体配体：4-氨基-1,2,4,5-四氢-2-苯并氮杂卓-3-酮（Aba）支架的应用。

Novel selective human melanocortin-3 receptor ligands: use of the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffold.

作者信息

Ballet Steven, Mayorov Alexander V, Cai Minying, Tymecka Dagmara, Chandler Kevin B, Palmer Erin S, Rompaey Karolien Van, Misicka Aleksandra, Tourwé Dirk, Hruby Victor J

机构信息

Department of Organic Chemistry, Vrije Universiteit Brussel, B-1050 Brussels, Belgium.

出版信息

Bioorg Med Chem Lett. 2007 May 1;17(9):2492-8. doi: 10.1016/j.bmcl.2007.02.020. Epub 2007 Feb 9.

DOI:10.1016/j.bmcl.2007.02.020
PMID:17314042
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2442462/
Abstract

In search of new selective antagonists and/or agonists for the human melanocortin receptor subtypes hMC1R to hMC5R to elucidate the specific biological roles of each GPCR, we modified the structures of the superagonist MT-II (Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH(2)) and the hMC3R/hMC4R antagonist SHU9119 (Ac-Nle-c[Asp-His-D-Nal(2')-Arg-Trp-Lys]-NH(2)) by replacing the His-d-Phe and His-d-Nal(2') fragments in MT-II and SHU9119, respectively, with Aba-Xxx (4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one-Xxx) dipeptidomimetics (Xxx=D-Phe/pCl-D-Phe/D-Nal(2')). Employment of the Aba mimetic yielded novel selective high affinity hMC3R and hMC3R/hMC5R antagonists.

摘要

为了寻找针对人类黑皮质素受体亚型hMC1R至hMC5R的新型选择性拮抗剂和/或激动剂，以阐明每种G蛋白偶联受体（GPCR）的特定生物学作用，我们通过分别用Aba-Xxx（4-氨基-1,2,4,5-四氢-2-苯并氮杂卓-3-酮-Xxx）二肽模拟物（Xxx = D-苯丙氨酸/pCl-D-苯丙氨酸/D-萘丙氨酸(2')）取代MT-II和SHU9119中的His-d-苯丙氨酸和His-d-萘丙氨酸(2')片段，对超级激动剂MT-II（Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH(2)）和hMC3R/hMC4R拮抗剂SHU9119（Ac-Nle-c[Asp-His-D-Nal(2')-Arg-Trp-Lys]-NH(2)）的结构进行了修饰。使用Aba模拟物产生了新型的选择性高亲和力hMC3R和hMC3R/hMC5R拮抗剂。

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Design of novel melanotropin agonists and antagonists with high potency and selectivity for human melanocortin receptors.新型促黑素激动剂和拮抗剂的设计，对人黑素皮质素受体具有高效力和选择性。
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