Vincent Fabien, Acevedo Alejandra, Nguyen Margaret T, Dourado Michelle, DeFalco Jeff, Gustafson Amy, Spiro Peter, Emerling Daniel E, Kelly Michael G, Duncton Matthew A J
In Vitro Pharmacology Department, Renovis, Inc., South San Francisco, CA 94080, USA.
Biochem Biophys Res Commun. 2009 Nov 20;389(3):490-4. doi: 10.1016/j.bbrc.2009.09.007. Epub 2009 Sep 6.
TRPV4, a close relative of the vanilloid receptor TRPV1, is activated by diverse modalities such as endogenous lipid ligands, hypotonicity, protein kinases and, possibly, mechanical inputs. While its multiple roles in vivo are being explored with KO mice and selective agonists, there is a dearth of selective antagonists available to examine TRPV4 function. Herein we detail the use of a focused library of commercial compounds in order to identify RN-1747 and RN-1734, a pair of structurally related small molecules endowed with TRPV4 agonist and antagonist properties, respectively. Their activities against human, rat and mouse TRPV4 were characterized using electrophysiology and intracellular calcium influx. Significantly, antagonist RN-1734 was observed to completely inhibit both ligand- and hypotonicity-activated TRPV4. In addition, RN-1734 was found to be selective for TRPV4 in a TRP selectivity panel including TRPV1, TRPV3 and TRPM8, and could thus be a valuable pharmacological probe for TRPV4 studies.
瞬时感受器电位香草酸受体4（TRPV4）是香草酸受体TRPV1的近亲，可被多种刺激激活，如内源性脂质配体、低渗、蛋白激酶，可能还有机械刺激。虽然利用基因敲除小鼠和选择性激动剂正在探索其在体内的多种作用，但目前缺乏用于研究TRPV4功能的选择性拮抗剂。在此，我们详细介绍了使用一个集中的商业化合物库，以鉴定RN - 1747和RN - 1734，这是一对结构相关的小分子，分别具有TRPV4激动剂和拮抗剂特性。利用电生理学和细胞内钙内流对它们针对人、大鼠和小鼠TRPV4的活性进行了表征。值得注意的是，观察到拮抗剂RN - 1734能完全抑制配体和低渗激活的TRPV4。此外，在包括TRPV1、TRPV3和TRPM8的TRP选择性检测中，发现RN - 1734对TRPV4具有选择性，因此可能是用于TRPV4研究的有价值的药理学探针。
