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 and Richard B. Silverman ()
Additional contact information
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
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
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

Nature Communications, 2012, vol. 3, issue 1, 1-7

Abstract: 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.

Date: 2012
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/ncomms2149 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms2149

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms2149

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().