Referenced in: none

Automatically associated channels: Cav1.3

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

Authors: Soosung Kang, Garry Cooper, Sara F Dunne, Brendon Dusel, Chi-Hao Luan, D James Surmeier, Richard B Silverman

Journal, date & volume: Nat Commun, 2012 , 3, 1146

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23093183

Abstract
L-type calcium channels expressed in the brain are heterogeneous. The predominant class of L-type calcium channels has a Ca(V)1.2 pore-forming subunit. L-type calcium channels with a Ca(V)1.3 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 Ca(V)1.3 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(V)1.3 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 Ca(V)1.3 L-type calcium channel antagonist. The biological relevance was confirmed by whole-cell patch-clamp electrophysiology. These studies describe the first highly selective Ca(V)1.3 L-type calcium channel antagonist and point to a novel therapeutic strategy for Parkinson's disease.