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., ...More

PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, vol.467, no.6, pp.1237-1247, 2015 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 467 Issue: 6
  • Publication Date: 2015
  • Doi Number: 10.1007/s00424-014-1566-3
  • Journal Name: PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.1237-1247
  • Keywords: Calcium channels, 1,4-Dihydropyridine, Pain, L-type, T-type, IDIOPATHIC GENERALIZED EPILEPSIES, SENSORY NEURONS, DIHYDROPYRIDINE BINDING, ABSENCE EPILEPSY, RECEPTOR-SITE, CA2+ CHANNELS, SCIATIC-NERVE, RAT MODEL, TARGETS, DETERMINANTS
  • Hacettepe University Affiliated: Yes

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 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.