title: CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease.
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.
authors.affiliation: Department of Chemistry, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208, USA.
authors.forename: Soosung
authors.initials: S
authors.lastname: Kang
authors.forename: Garry
authors.initials: G
authors.lastname: Cooper
authors.forename: Sara F
authors.initials: SF
authors.lastname: Dunne
authors.forename: Brendon
authors.initials: B
authors.lastname: Dusel
authors.forename: Chi-Hao
authors.initials: CH
authors.lastname: Luan
authors.forename: D James
authors.initials: DJ
authors.lastname: Surmeier
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000818:Animals; D001463:Barbiturates / Q000494:pharmacology* / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D003461:Crystallography; D004353:Drug Evaluation, Preclinical / Q000379:methods; D057809:HEK293 Cells / Q000187:drug effects; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D010300:Parkinson Disease / Q000188:drug therapy*; D018408:Patch-Clamp Techniques; D011817:Rabbits; D051381:Rats; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: C581561:1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione; D001463:Barbiturates; C472073:CACNA1D protein, human; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D054852:Small Molecule Libraries