INRS-Institut Armand-Frappier, Institut national de la recherche scientifique, Université du Québec , Ville de Laval, Québec, QC H7V 1B7, Canada.
J Med Chem. 2013 Dec 12;56(23):9612-22. doi: 10.1021/jm401153j. Epub 2013 Nov 26.
Urotensin II (UII) and its paralog peptide, urotensin II-related peptide (URP), exert not only common but also divergent actions through the activation of UT, a specific membrane-bound receptor that belongs to the 1A G protein-coupled receptor subclass. In this study, we have designed and synthesized new URP analogues in which the intracyclic Trp residue was replaced with natural, unnatural, and constrained amino acids to determine important physicochemical features for receptor binding and activation. The biological data, highlighting the potent agonistic behavior of [Tiq(4)]URP and [Tpi(4)]URP, also suggest that the Trp residue, and more specifically the indole ring, is not critical for receptor interaction and could in fact be involved in the intramolecular stabilization of the bioactive conformation of URP. Finally, these analogues, which are intracyclic constrained URP-based agonists, could represent useful pharmacological tools for the study of the urotensinergic system.
尾加压素 II（UII）及其同工肽尾加压素 II 相关肽（URP）通过激活 UT 发挥作用，UT 是一种特异性的膜结合受体，属于 1A G 蛋白偶联受体亚类。在这项研究中，我们设计并合成了新的 URP 类似物，其中环内色氨酸残基被天然、非天然和约束性氨基酸取代，以确定与受体结合和激活相关的重要理化特征。生物学数据突出了 [Tiq(4)]URP 和 [Tpi(4)]URP 的强效激动作用，也表明色氨酸残基，更具体地说是吲哚环，对于受体相互作用不是关键的，实际上可能参与 URP 生物活性构象的分子内稳定。最后，这些类似物是基于环状约束 URP 的内源性激动剂，可能成为研究尾加压素能系统的有用药理学工具。
