Urotensin-II receptor ligands. From agonist to antagonist activity
Urotensin-II receptor ligands. From agonist to antagonist activity
复制标题
DOI：
10.1021/jm058043j
复制
发表时间：
2005-11-17
影响因子：
7.3
通讯作者：
Novellino, E
中科院分区：
文献类型：
--
作者：
Grieco, P;Carotenuto, A;Novellino, E
尾加压素 II (U-II) 是一种二硫桥肽激素，最近被鉴定为 G 蛋白偶联受体的配体。人 U-II (H-Glu-Thr-Pro-Asp-cyclo[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) 被描述为迄今为止发现的最有效的血管收缩化合物。我们最近发现了一种名为 P5U 的 hU-II 超级激动剂和一种名为 urantide 的化合物，后者是迄今为止描述的最有效的 UT 受体肽拮抗剂。我们之前的构象研究表明，hU-II及其具有激动剂活性的类似物在各向异性SDS膜样环境中采用明确的II型β-发夹结构。这种结构排列允许 Trp(7)、Lys(8) 和 Tyr(9) 侧链之间紧密接触，这是获得完全激动剂活性的基础。在这里，我们报告了一项关于对 UT 受体具有激动剂/拮抗剂活性的新类似物的广泛 SAR 研究。我们研究了它们的生物活性，并通过光谱和计算方法进行了构象分析。我们的目标是获得一个基于结构的模型，能够解释这些配体的激动剂/拮抗剂功能转换。
Urotensin II (U-II) is a disulfide bridged peptide hormone recently identified as the ligand of a G-protein-coupled receptor. Human U-II (H-Glu-Thr-Pro-Asp-cyclo[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) has been described as the most potent vasoconstrictor compound identified to date. We have recently identified both a superagonist of hU-II termed P5U and the compound termed urantide, which is the most potent UT receptor peptide antagonist described to date. Our previous conformational studies showed that hU-II and its analogues with agonist activity adopt a well-defined type II' beta-hairpin structure in anisotropic SDS membrane-like environment. This structural arrangement allows tight contact among the Trp(7), Lys(8), and Tyr(9) side chains, which is fundamental to obtain full agonist activity. Here, we report an extensive SAR study on new analogues with agonist/antagonist activity on UT receptor. We investigated their biological activity and performed a conformational analysis by spectroscopic and computational methods. Our goal is to obtain a structure-based model able to explain the agonist/antagonist functional switching of these ligands.