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Effect of non-steroidal anti-inflammatory drugs and new fenamate analogues on TRPC4 and TRPC5 channels

Jiang, Hongni; Zeng, Bo; Chen, Gui-Lan; Bot, David; Eastmond, Sarah; Elsenussi, Sandra E; Atkin, Stephen L; Boa, Andrew N; Xu, Shang-Zhong

Authors

Hongni Jiang

Bo Zeng

Gui-Lan Chen

David Bot

Sarah Eastmond

Sandra E Elsenussi

Stephen L Atkin

Shang-Zhong Xu



Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used anti-inflammatory therapeutic agents,among which the fenamate analogues play important roles in regulating intracellular Ca<sup>2+</sup> transient and ion channels. However, the effect of NSAIDs on TRPC4 and TRPC5 is still unknown. To understand thestructure–activity of fenamate analogues on TRPC channels, we have synthesized a series of fenamateanalogues and investigated their effects on TRPC4 and TRPC5 channels.Human TRPC4 and TRPC5 cDNAs in tetracycline-regulated vectors were transfected into HEK293T-REx cells. The whole cell current and Ca<sup>2+</sup> movement were recorded by patch clamp and calciumimaging, respectively.Flufenamic acid (FFA), mefenamic acid (MFA), niflumic acid (NFA) and diclofenac sodium (DFS) showed inhibition on TRPC4 and TRPC5 channels in a concentration-dependent manner. The potencywas FFA > MFA > NFA > DFS. Modification of 2-phenylamino ring by substitution of the trifluoromethylgroup in FFA with –F, –CH<sub>3</sub>, –OCH<sub>3</sub>, –OCH<sub>2</sub>CH<sub>3</sub>, –COOH, and –NO2 led to the changes in their channelblocking activity. However, 2-(20-methoxy-50-methylphenyl)aminobenzoic acid stimulated TRPC4 andTRPC5 channels. Selective COX1-3 inhibitors (aspirin, celecoxib, acetaminophen, and indomethacin)had no effect on the channels. Longer perfusion (>5 min) with FFA (100 mM) and MFA (100 mM) caused apotentiation of TRPC4 and TRPC5 currents after their initial blocking effects that appeared to be partiallymediated by the mitochondrial Ca<sup>2+</sup> release.Our results suggest that fenamate analogues are direct modulators of TRPC4 and TRPC5 channels. Thesubstitution pattern and conformation of the 2-phenylamino ring could alter their blocking activity,which is important for understanding fenamate pharmacology and new drug development targeting theTRPC channels.

Journal Article Type Article
Publication Date Apr 1, 2012
Journal Biochemical Pharmacology
Print ISSN 0006-2952
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 83
Issue 7
Pages 923-931
APA6 Citation Jiang, H., Zeng, B., Chen, G., Bot, D., Eastmond, S., Elsenussi, S. E., …Xu, S. (2012). Effect of non-steroidal anti-inflammatory drugs and new fenamate analogues on TRPC4 and TRPC5 channels. Biochemical Pharmacology, 83(7), 923-931. https://doi.org/10.1016/j.bcp.2012.01.014
DOI https://doi.org/10.1016/j.bcp.2012.01.014
Keywords Non-steroidal anti-inflammatory drugs, Calcium channel, TRPC, Fenamate analogues, 2-Aminoethoxydiphenyl borate, REF 2014 submission**
Publisher URL http://www.sciencedirect.com/science/article/pii/S0006295212000615?via%3Dihub
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