CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease

Soosung Kang, Garry Cooper, Sara F. Dunne, Brendon Dusel, Chi Hao Luan, D. James Surmeier, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

L-type calcium channels expressed in the brain are heterogeneous. The predominant class of L-type calcium channels has a CaV1.2 pore-forming subunit. L-type calcium channels with a CaV1.3 pore-forming subunit are much less abundant, but have been implicated in the generation of mitochondrial oxidant stress underlying pathogenesis in Parkinson's disease. Thus, selectively antagonizing CaV1.3 L-type calcium channels could provide a means of diminishing cell loss in Parkinson's disease without producing side effects accompanying general antagonism of L-type calcium channels. However, there are no known selective antagonists of Ca V1.3 L-type calcium channel. Here we report high-throughput screening of commercial and 'in-house' chemical libraries and modification of promising hits. Pyrimidine-2,4,6-triones were identified as a potential scaffold; structure-activity relationship-based modification of this scaffold led to 1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione (8), a potent and highly selective CaV1.3 L-type calcium channel antagonist. The biological relevance was confirmed by whole-cell patch-clamp electrophysiology. These studies describe the first highly selective Ca V1.3 L-type calcium channel antagonist and point to a novel therapeutic strategy for Parkinson's disease.

Original languageEnglish (US)
Article number1146
JournalNature communications
Volume3
DOIs
StatePublished - 2012

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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