Synthesis and evaluation of 1,4-dihydropyridine derivatives with calcium channel blocking activity

Chris Bladen, Miyase Gözde Gündüz, Rahime Şimşek, Cihat Şafak, Gerald W. Zamponi

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1355-1363
Number of pages9
JournalPflugers Archiv European Journal of Physiology
Volume466
Issue number7
DOIs
Publication statusPublished - 1 Jul 2014
Externally publishedYes

Keywords

  • Calcium channels
  • 1,4-Dihydropyridine
  • Cardiovascular
  • Hypertension
  • L-type
  • T-type
  • Aldosterone secretion
  • Aldosterone secretion.

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