Synthesis and Evaluation of 1,4-Dihydropyridine Derivatives with Calcium Channel Blocking Activity

Bladen C., GÜNDÜZ M. G., ŞİMŞEK R., Safak C., Zamponi G. W.

PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, vol.466, no.7, pp.1355-1363, 2014 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 466 Issue: 7
  • Publication Date: 2014
  • Doi Number: 10.1007/s00424-013-1376-z
  • Journal Name: PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.1355-1363
  • Keywords: Calcium channels, 1,4-Dihydropyridine, Cardiovascular, Hypertension, L-type, T-type, Aldosterone secretion, DIHYDROPYRIDINE BINDING, MOLECULAR DETERMINANTS, CA2+ CHANNELS, RECEPTOR-SITE, INHIBITION, COMPONENTS, GENE
  • Hacettepe University Affiliated: Yes

Abstract

1,4-Dihydropyridines (DHPs) are an important class of L-type calcium channel blockers that are used to treat conditions such as hypertension and angina. Their primary target in the cardiovascular system is the Cav1.2 L-type calcium channel isoform, however, a number of DHPs also block low-voltage-activated T-type calcium channels. Here, we describe the synthesis of a series of novel DHP derivatives that have a condensed 1,4-DHP ring system (hexahydroquinoline) and report on their abilities to block both L- and T-type calcium channels. Within this series of compounds, modification of a key ester moiety not only regulates the blocking affinity for both L- and T-type channels, but also allows for the development of DHPs with 30-fold selectivity for T-type channels over the L-type. Our data suggest that a condensed dihydropyridine-based scaffold may serve as a pharmacophore for a new class of T-type selective inhibitors.