Ca_V1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease

L-type calcium channels expressed in the brain are heterogeneous. The predominant class of L-type calcium channels has a Ca_V1.2 pore-forming subunit. L-type calcium channels with a Ca_V1.3 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_V1.3 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 Ca_V1.3 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.