Identification of small-molecule agonists of human relaxin family receptor 1 (RXFP1) by using a homogenous cell-based cAMP assay.
Identification of small-molecule agonists of human relaxin family receptor 1 (RXFP1) by using a homogenous cell-based cAMP assay.
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DOI：
10.1177/1087057112469406
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发表时间：
2013-07
影响因子：
--
通讯作者：
Agoulnik AI
中科院分区：
文献类型：
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作者：
Chen CZ;Southall N;Xiao J;Marugan JJ;Ferrer M;Hu X;Jones RE;Feng S;Agoulnik IU;Zheng W;Agoulnik AI
松弛激素参与多种生物功能，包括女性生殖和分娩，心血管、肾脏、肺和肝脏功能的调节。它调节细胞外基质重塑、细胞侵袭、增殖、分化和整体组织稳态。G蛋白偶联受体（GPCR） RXFP1，松弛素家族受体1，是一个同源的松弛素受体，主要通过环AMP第二信使发出信号。虽然受体的激动剂可能具有广泛的药理学用途，但到目前为止，还没有关于松弛素受体的小分子激动剂的报道。在这里，我们报告了基于均质细胞HTRF cAMP检测技术的RXFP1激动剂筛选定量高通量平台的开发。两个结构相似的小分子从超过365,677种化合物中独立鉴定出来。这两种化合物对转染了不相关的GPCR加压素1b受体的HEK293T细胞都没有活性。这些小分子激动剂对RXFP2受体也表现出选择性，为未来选择性松弛素受体激动剂的药物化学优化提供了基础。
The relaxin hormone is involved in a variety of biological functions including female reproduction and parturition, regulation of cardiovascular, renal, pulmonary, and hepatic functions. It regulates extracellular matrix remodeling, cell invasiveness, proliferation, differentiation, and overall tissue homeostasis. The G protein-coupled receptor (GPCR) RXFP1, relaxin family receptor 1, is a cognate relaxin receptor that mainly signals through cyclic AMP second messenger. While agonists of the receptor could have a wide range of pharmacological utility, up to date, there are no reported small molecule agonists for relaxin receptors. Here, we report the development of quantitative high-throughput platform for RXFP1 agonist screen based on homogenous cell-based HTRF cAMP assay technology. Two small molecules of similar structure were independently identified from a screen of more than 365,677 compounds. Neither compound showed activity in a counter screen with HEK293T cells transfected with an unrelated GPCR vasopressin 1b receptor. These small molecule agonists also demonstrated selectivity against the RXFP2 receptor, providing a basis for future medicinal chemistry optimization of selective relaxin receptor agonists.