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

Author

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  • Soosung Kang

    (Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University)

  • Garry Cooper

    (Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University
    Feinberg School of Medicine, Northwestern University)

  • Sara F. Dunne

    (High-Throughput Analysis Laboratory, Chemistry of Life Processes Institute, Northwestern University)

  • Brendon Dusel

    (High-Throughput Analysis Laboratory, Chemistry of Life Processes Institute, Northwestern University)

  • Chi-Hao Luan

    (High-Throughput Analysis Laboratory, Chemistry of Life Processes Institute, Northwestern University
    Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University)

  • D. James Surmeier

    (Feinberg School of Medicine, Northwestern University)

  • Richard B. Silverman

    (Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University
    Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University)

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 CaV1.3 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 CaV1.3 L-type calcium channel antagonist and point to a novel therapeutic strategy for Parkinson's disease.

Suggested Citation

  • Soosung Kang & Garry Cooper & Sara F. Dunne & Brendon Dusel & Chi-Hao Luan & D. James Surmeier & Richard B. Silverman, 2012. "CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease," Nature Communications, Nature, vol. 3(1), pages 1-7, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms2149
    DOI: 10.1038/ncomms2149
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    Cited by:

    1. Pietro Mesirca & Jean Chemin & Christian Barrère & Eleonora Torre & Laura Gallot & Arnaud Monteil & Isabelle Bidaud & Sylvie Diochot & Michel Lazdunski & Tuck Wah Soong & Stéphanie Barrère-Lemaire & M, 2024. "Selective blockade of Cav1.2 (α1C) versus Cav1.3 (α1D) L-type calcium channels by the black mamba toxin calciseptine," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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