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

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

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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 2+ transient and ion channels. However, the effect of NSAIDs on TRPC4 and TRPC5 is still unknown. To understand the structure-activity of fenamate analogues on TRPC channels, we have synthesized a series of fenamate analogues and investigated their effects on TRPC4 and TRPC5 channels. Human TRPC4 and TRPC5 cDNAs in tetracycline- regulated vectors were transfected into HEK293 T-REx cells. The whole cell current and Ca 2+ movement were recorded by patch clamp and calcium imaging, 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 potency was FFA > MFA > NFA > DFS. Modification of 2-phenylamino ring by substitution of the trifluoromethyl group in FFA with F, CH 3, OCH 3, OCH 2CH 3, COOH, and NO 2 led to the changes in their channel blocking activity. However, 2-(2′-methoxy-5′-methylphenyl) aminobenzoic acid stimulated TRPC4 and TRPC5 channels. Selective COX1-3 inhibitors (aspirin, celecoxib, acetaminophen, and indomethacin) had no effect on the channels. Longer perfusion (>5 min) with FFA (100 μM) and MFA (100 μM) caused a potentiation of TRPC4 and TRPC5 currents after their initial blocking effects that appeared to be partially mediated by the mitochondrial Ca 2+ release. Our results suggest that fenamate analogues are direct modulators of TRPC4 and TRPC5 channels. The substitution 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 the TRPC channels.

Original languageEnglish
Pages (from-to)923-931
Number of pages9
JournalBiochemical Pharmacology
Volume83
Issue number7
DOIs
Publication statusPublished - 1 Apr 2012
Externally publishedYes

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Keywords

  • 2-Aminoethoxydiphenyl borate
  • Calcium channel
  • Fenamate analogues
  • Non-steroidal anti-inflammatory drugs
  • TRPC

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Jiang, H., Zeng, B., Chen, G. L., Bot, D., Eastmond, S., Elsenussi, S. E., Atkin, S., Boa, A. N., & Xu, S. Z. (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