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

Research output: Contribution to journalArticlepeer-review

108 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
Article number1146
JournalNature Communications
Volume3
DOIs
StatePublished - 2012

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