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ABSTRACT: CaV1.3 L-type calcium channels (LTCCs) have been a potential target for Parkinson's disease since calcium ion influx through the channel was implicated in the generation of mitochondrial oxidative stress, causing cell death in the dopaminergic neurons. Selective inhibition of CaV1.3 over other LTCC isoforms, especially CaV1.2, is critical to minimize potential side effects. We recently identified pyrimidinetriones (PYTs) as a CaV1.3-selective scaffold; here we report the structure-activity relationship of PYTs with both CaV1.3 and CaV1.2 LTCCs. By varying the substituents on the cyclopentyl and arylalkyl group of PYT, SAR studies allowed characterization of the CaV1.3 and CaV1.2 LTCCs binding sites. The SAR also identified four important moieties that either retain selectivity or enhance binding affinity. Our study represents a significant enhancement of the SAR of PYTs at CaV1.3 and CaV1.2 LTCCs and highlights several advances in the lead optimization and diversification of this family of compounds for drug development.
Journal of Medicinal Chemistry 05/2013; · 4.80 Impact Factor
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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.
Nature Communications 10/2012; 3:1146. · 7.40 Impact Factor
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ABSTRACT: L-type Ca(2+) channels in mammalian brain neurons have either a Ca(V)1.2 or Ca(V)1.3 pore-forming subunit. Recently, it was shown that Ca(V)1.3 Ca(2+) channels underlie autonomous pacemaking in adult dopaminergic neurons in the substantia nigra pars compacta, and this reliance renders them sensitive to toxins used to create animal models of Parkinson's disease. Antagonism of these channels with the dihydropyridine antihypertensive drug isradipine diminishes the reliance on Ca(2+) and the sensitivity of these neurons to toxins, pointing to a potential neuroprotective strategy. However, for neuroprotection without an antihypertensive side effect, selective Ca(V)1.3 channel antagonists are required. In an attempt to identify potent and selective antagonists of Ca(V)1.3 channels, 124 dihydropyridines (4-substituted-1,4-dihydropyridine-3,5-dicarboxylic diesters) were synthesized. The antagonism of heterologously expressed Ca(V)1.2 and Ca(V)1.3 channels was then tested using electrophysiological approaches and the FLIPR Calcium 4 assay. Despite the large diversity in substitution on the dihydropyridine scaffold, the most Ca(V)1.3 selectivity was only about twofold. These results support a highly similar dihydropyridine binding site at both Ca(V)1.2 and Ca(V)1.3 channels and suggests that other classes of compounds need to be identified for Ca(V)1.3 selectivity.
Bioorganic & medicinal chemistry 03/2010; 18(9):3147-58. · 2.82 Impact Factor
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Bioorganic & Medicinal Chemistry. 18(9):3147-3158.
