Selectivity of blocking of low- versus high-voltage activated calcium currents by the dihydropyridine derivatives Bay E5759 and Bay A4339 in neuroblastoma-glioma NG 108-15 cells.

摘要

Beneficial therapeutic effects of dihydropyridine derivatives in cardiovascular and neurological disorders are often associated with selective L-type Ca(2+)channel blockade. Here the new dihydropyridine derivatives Bay E5759 (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid ethyl-1-methylethyl ester) and Bay A4339 (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl-ester) were tested for their potency and selectivity of blocking of Ba(2+)currents mediated by low-(LVACC)vs high-voltage activated Ca(2+)channels (HVACC) in neuroblastoma-glioma hybrid cells. Nisoldipine and mibefradil served as reference compounds. Bay E5759 and Bay A4339 blocked HVACC at low nanomolar concentrations, whereas LVACC was hardly reduced at up to 10 &mgr; M. The order of potency for blockade of HVACC was Bay E5759 (IC(50): 0.4 nM) > Bay A4339 (2.5 nM) approximately = nisoldipine (4 nM) mibefradil (3.8 &mgr; M). Thus Bay E5759 and Bay A4339 are highly potent and selective blockers of HVACC, presumably L-type Ca(2+)channels. Copyright 2001 Academic Press.