Sandra E Elsenussi
Pharmacological comparison of novel synthetic fenamate analogues with econazole and 2-APB on the inhibition of TRPM2 channels
Elsenussi, Sandra E; Boa, Andrew N; Chen, Gui-Lan; Xu, Sam; Zeng, B.; Boa, Andrew; Eastmond, Sarah; Elsenussi, Sandra E.; Boa, Andrew N.; Xu, Shang-Zhong
Andrew N Boa
Sam Xu S.Xu@hull.ac.uk
Sandra E. Elsenussi
BACKGROUND: Fenamate analogues, econazole and 2-APB are inhibitors of TRPM2 channels, which have been used as research tools. However, these compounds have different chemical structures and therapeutic applications. Here we aimed to investigate the pharmacological profile of TRPM2 channels by application of new synthesized fenamate analogues and the existing channel blockers.EXPERIMENTAL APPROACH: Human TRPM2 in tetracycline-regulated pcDNA4/TO vectors was transfected into HEK293 T-REx cells and the expression was induced by tetracycline. The whole-cell current was recorded by patch clamp. Ca2+ influx or release was monitored by Ca2+ dye.KEY RESULTS Flufenamic acid (FFA), mefenamic acid (MFA) and niflumic acid (NFA) showed significant inhibition on TRPM2 current in a concentration-dependent manner. The potency was FFA>MFA=NFA. Modification of the 2-phenylamino ring by substitution of the trifluoromethyl group in FFA with -CH3, -F, -CF3, -OCH3, -OCH2CH3, -COOH, and -NO2 at various positions led to reduced potency in their channel blocking activity. The conservative substitution of 3-CF3 in FFA by -CH3 (3-MFA), however, gave the most potent fenamate analogue with an IC50 of 76 µM which is similar to that of FFA, but had no effect on Ca2+ release that FFA possessed. 3-MFA and FFA inhibited the channel intracellularly. Econazole and 2-APB showed the nonselectivity by interfering cytosolic Ca2+ movement, and econazole also evoked a non-selective current.CONCLUSIONS AND IMPLICATIONS: Our results suggest that the fenamate analogue 3-MFA is more selective than other TRPM2 channel blockers. The use of FFA, 2-APB and econazole as TRPM2 channel blockers should be cautious, as the three compounds can interfere with intracellular Ca2+ movement.
Chen, G., Zeng, B., Eastmond, S., Elsenussi, S. E., Boa, A. N., & Xu, S. (2012). Pharmacological comparison of novel synthetic fenamate analogues with econazole and 2-APB on the inhibition of TRPM2 channels. British Journal of Pharmacology, 167(6), 1232-1243. https://doi.org/10.1111/j.1476-5381.2012.02058.x
|Journal Article Type||Article|
|Acceptance Date||May 21, 2012|
|Online Publication Date||May 30, 2012|
|Journal||British Journal of Pharmacology|
|Peer Reviewed||Peer Reviewed|
|Keywords||Non‐steroidal anti‐inflammatory drugs; Calcium channel; TRPM2; Fenamate analogues; Econazole; 2‐aminoethoxydiphenyl borate|
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