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


Bladen C., Gadotti V. M. , GÜNDÜZ M. G. , Berger N. D. , ŞİMŞEK R. , Safak C., ...Daha Fazla

PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, cilt.467, ss.1237-1247, 2015 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 467 Konu: 6
  • Basım Tarihi: 2015
  • Doi Numarası: 10.1007/s00424-014-1566-3
  • Dergi Adı: PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
  • Sayfa Sayıları: ss.1237-1247

Özet

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 Ca(v)3.2 over Ca(v)1.2 L-type channels. The effects of the two lead compounds, termed N10 and N12, on Ca(v)3.2 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 Ca(v)3.2 null mice. Altogether, our data reveal a novel class of T-type channel blocking DHPs for potential pain therapies.