L-Type calcium channels (LTCCs) expressed in the brain are heterogeneous. The predominant class of LTCC has a CaV1.2 pore-forming subunit. LTCCs 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 (PD). Thus, selectively antagonizing CaV1.3 LTCCs could provide a means of diminishing cell loss in PD without producing side effects accompanying general antagonism of LTCCs. To fill this gap, high-throughput screening of commercial and 'in-house' chemical libraries and modification of promising hits was carried out. Pyrimidine-2,4,6-triones were identified as a potential scaffold; structure-activity relationship-based modification of this scaffold led to a potent and highly selective (>600-fold) CaV1.3  LTCC antagonist. The biological relevance was confirmed by whole-cell patch-clamp electrophysiology.  Homology modeling and computer modeling were used to enhance the potency and selectivity.  Studies directed at the mechanism of action of these compounds are being carried out. These are the first highly selective CaV1.3 LTCC antagonists and point to a novel therapeutic strategy for PD that slows the progression of the disease rather than just treats the symptoms.

Ca<sub>V</sub>1.3-selective L-type calcium channel antagonists, novel therapeutics to slow the progression of Parkinson's disease

245th National Meeting (2013)

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CaV1.3-selective L-type calcium channel antagonists, novel therapeutics to slow the progression of Parkinson's disease

Ca_V1.3-selective L-type calcium channel antagonists, novel therapeutics to slow the progression of Parkinson's disease