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Insights into the Molecular Determinants Involved in Urocontrin and Urocontrin A Action.
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2020-08-20 , DOI: 10.1021/acsmedchemlett.0c00223
Etienne Billard 1 , David Chatenet 1
Affiliation  

In the past few years, we have identified two allosteric modulators of the urotensinergic system with probe-dependent action, termed Urocontrin (UC) and Urocontrin A (UCA). Such action is atypical and important since it will allow us to understand the specific function of the functionally selective cognate ligands of this system, namely urotensin II and urotensin II-related peptide. Delineating the molecular determinants involved in this particular behavior would represent an important step toward designing small molecules suitable for pharmacologic and/or therapeutic intervention. Hence, we undertook an exploratory research by replacing the Trp4 residue of URP with several para-substituted phenylalanine amino acids in order to get a grasp on the required nature, distance, and orientation of the side chain of this residue for allosteric modulatory action. We found that the position of the second aromatic group is crucial, and we identified two new allosteric modulators: [Trip4]URP and [Phe(pPy-4)4]URP with probe-dependent action.

中文翻译:

深入了解 Urocontrin 和 Urocontrin A 作用中涉及的分子决定因素。

在过去几年中,我们已经确定了两种具有探针依赖性作用的尿加压素系统变构调节剂,称为尿凝素 (UC) 和尿凝素 A (UCA)。这种作用是非典型和重要的,因为它将使我们能够了解该系统的功能选择性同源配体的特定功能,即尿加压素 II 和尿加压素 II 相关肽。描绘参与这种特定行为的分子决定因素将代表设计适合药理和/或治疗干预的小分子的重要一步。因此,我们通过替换 Trp 4进行了探索性研究URP 的残基与几个对位取代的苯丙氨酸氨基酸,以便掌握该残基侧链的所需性质、距离和方向,以实现变构调节作用。我们发现第二个芳族基团的位置至关重要,并且我们确定了两个新的变构调节剂:[Trip 4 ]URP 和 [Phe(pPy-4) 4 ]URP 具有探针依赖性作用。
更新日期:2020-09-10
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