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1,4-Dihydropyridine derivatives with T-type calcium channel blocking activity attenuate inflammatory and neuropathic pain

  • Ion channels, receptors and transporters
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Abstract

We have recently identified a class of dihydropyridine (DHP) analogues with 30-fold selectivity for T-type over L-type calcium channels that could be attributed to a modification of a key ester moiety. Based on these results, we examined a second series of compounds with similar attributes to determine if they had enhanced affinity for T-type channels. Whole-cell patch clamp experiments in transfected tsA-201 cells were used to screen these DHP derivatives for high affinity and selectivity for Cav3.2 over Cav1.2 L-type channels. The effects of the two lead compounds, termed N10 and N12, on Cav3.2 channel activity and gating were characterized in detail. When delivered intrathecally or intraperitoneally, these compounds mediated analgesia in a mouse model of acute inflammatory pain. The best compound from the initial screening, N12, was also able to reverse mechanical hyperalgesia produced by nerve injury. The compounds were ineffective in Cav3.2 null mice. Altogether, our data reveal a novel class of T-type channel blocking DHPs for potential pain therapies.

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Acknowledgments

This work was supported by operating grants to GWZ from the Canadian Institutes of Health Research. GWZ is a Canada Research Chair and an Alberta Innovates–Health Solutions (AI-HS) Scientist. CB holds a T. Chen Fong studentship and an AI-HS studentship award. VG holds a MITACS Elevate fellowship. NDB holds an AI-HS summer studentship award.

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Authors and Affiliations

  1. Department of Physiology & Pharmacology, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4 N1, Canada

    Chris Bladen, Vinicius M. Gadotti, N. Daniel Berger & Gerald W. Zamponi

  2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey

    Miyase G. Gündüz, Rahime Şimşek & Cihat Şafak

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  1. Chris Bladen
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  2. Vinicius M. Gadotti
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Correspondence to Gerald W. Zamponi.

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Bladen, C., Gadotti, V.M., Gündüz, M.G. et al. 1,4-Dihydropyridine derivatives with T-type calcium channel blocking activity attenuate inflammatory and neuropathic pain. Pflugers Arch - Eur J Physiol 467, 1237–1247 (2015). https://doi.org/10.1007/s00424-014-1566-3

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