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

Beneficial therapeutic effects of dihydropyridine derivatives in cardiovasc ular and neurological disorders are often associated with selective L-type Ca2+ channel blockade. Here the new dihydropyridine derivatives Bay E5759 ( 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5- pyridinedicarboxylic acid e thyl-1-methylethyl ester) and Bay A4339 (1,4-dihydro-2,6-dimethyl-4-(3-nitr ophenyl)-3,5-pyridinedicarboxylic acid dimethyl-ester) were tested for thei r potency and selectivity of blocking of Ba2+ currents mediated by low-(LVA CC) vs high-voltage activated Ca2+ channels (HVACC) in neuroblastoma-glioma hybrid cells. Nisoldipine and mibefradil served as reference compounds. Ba y E5759 and Bay A4339 blocked HVACC at low nanomolar concentrations, wherea s LVACC was hardly reduced at up to 10 muM. The order of potency for blocka de of HVACC was Bay E5759 (IC50 :0.4 nM) > Bay A4339 (2.5 nM) congruent to nisoldipine (4 nM) much greater than mibefradil (3.8 muM). Thus Bay E5759 a nd Bay A4339 are highly potent and selective blockers of HVACC, presumably L-type Ca2+ channels. (C) 2001 Academic Press.