Discovery and Characterization of the First Nonpeptide Antagonists for the Relaxin-3/RXFP3 System.
Discovery and Characterization of the First Nonpeptide Antagonists for the Relaxin-3/RXFP3 System.
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DOI：
10.1021/acs.jmedchem.2c00508
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发表时间：
2022-06-09
影响因子：
7.3
通讯作者：
Jin, Chunyang
中科院分区：
文献类型：
--
作者：
Gay, Elaine A.;Guan, Dongliang;Van Voorhies, Kalynn;Vasukuttan, Vineetha;Mathews, Kelly M.;Besheer, Joyce;Jin, Chunyang
神经肽松弛素-3/RXFP 3系统参与许多重要的生理过程，如应激反应、食欲控制和奖励动机。迄今为止，RXFP 3的药理学研究仅限于肽配体。在这项研究中，我们报告了通过高通量筛选活动发现的第一个RXFP 3的小分子拮抗剂。对命中化合物的聚焦结构-活性关系研究产生了能够在一系列功能测定中抑制松弛素-3活性的RLX-33（33）。RLX-33对松弛素/胰岛素超家族中的两个相关成员RXFP 1和RXFP 4的RXFP 3具有选择性，并且具有用于行为评估的有利药代动力学特性。当腹膜内给予大鼠时，RLX-33阻断由RXFP 3选择性激动剂R3/I5诱导的食物摄入。总的来说，我们的研究结果表明，RLX-33代表了一种有前途的拮抗剂支架，用于开发靶向松弛素-3/RXFP3系统的药物。
The neuropeptide relaxin-3/RXFP3 system is involved in many important physiological processes such as stress responses, appetite control, and motivation for reward. To date, pharmacological studies of RXFP3 have been limited to peptide ligands. In this study, we report the discovery of the first small molecule antagonists of RXFP3 through a high throughput screening campaign. Focused structure-activity relationship studies of the hit compound resulted in RLX-33 (33) that was able to inhibit relaxin-3 activity in a battery of functional assays. RLX-33 is selective for RXFP3 over RXFP1 and RXFP4, two related members in the relaxin/insulin superfamily, and has favorable pharmacokinetic properties for behavioral assessment. When administered to rats intraperitoneally, RLX-33 blocked food intake induced by the RXFP3-selective agonist R3/I5. Collectively, our findings demonstrated that RLX-33 represents a promising antagonist scaffold for the development of drugs targeting the relaxin-3/RXFP3 system.
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影响因子：
7.3
作者：
German N;Decker AM;Gilmour BP;Gay EA;Wiley JL;Thomas BF;Zhang Y
通讯作者：
Zhang Y
DOI：
10.1124/jpet.104.073486
发表时间：
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作者：
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影响因子：
7.3
作者：
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