Antagonism of L-type Ca2+ channels CaV1.3 and Ca V1.2 by 1,4-dihydropyrimidines and 4H-pyrans as dihydropyridine mimics

Soosung Kang, Garry Cooper, Sara Fernandez Dunne, Chi-Hao Luan, Dalton James Surmeier Jr, Richard B Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

The L-type calcium channel (LTCC) CaV1.3 is regarded as a new potential therapeutic target for Parkinson's disease. Calcium influx through CaV1.3 LTCC during autonomous pacemaking in adult dopaminergic neurons of the substantia nigra pars compacta is related to the generation of mitochondrial oxidative stress in animal models. Development of a Ca V1.3 antagonist selective over CaV1.2 is essential because CaV1.2 pore-forming subunits are the predominant form of LTCCs and are abundant in the central nervous and cardiovascular systems. We have explored 1,4-dihydropyrimidines and 4H-pyrans to identify potent and selective antagonists of CaV1.3 relative to CaV1.2 LTCCs. A library of 36 dihydropyridine (DHP)-mimic 1,4-dihydropyrimidines and 4H-pyrans was synthesized, and promising chiral compounds were resolved. The antagonism studies of CaV1.3 and CaV1.2 LTCCs using DHP mimic compounds showed that dihydropyrimidines and 4H-pyrans are effective antagonists of DHPs for CaV1.3 LTCCs. Some 1,4-dihydropyrimidines are more selective than isradipine for CaV1.3 over CaV1.2, shown here by both calcium flux and patch-clamp electrophysiology experiments, where the ratio of antagonism is around 2-3. These results support the hypothesis that the modified hydrogen bonding donor/acceptors in DHP-mimic dihydropyrimidines and 4H-pyrans can interact differently with DHP binding sites, but, in addition, the data suggest that the binding sites of DHP in CaV1.3 and Ca V1.2 LTCCs are very similar.

Original languageEnglish (US)
Pages (from-to)4365-4373
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number14
DOIs
StatePublished - Jul 15 2013

Keywords

  • 1,4-Dihydropyrimidines
  • 4H-Pyrans
  • Antagonism
  • Ca1.2 Ca channel
  • Ca1.3 Ca channel
  • FLIPR (Fluorometric imaging plate reader)
  • L-type calcium channel
  • Parkinson's disease

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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