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 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 microM. 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 microM). Thus Bay E5759 and Bay A4339 are highly potent and selective blockers of HVACC, presumably L-type Ca(2+)channels.
Himmel
H M
HM
Department of Pharmacology and Toxicology, Carl Gustav Carus Medical School, Dresden University of Technology, Dresden, Germany.
Stengel
W
W
Ravens
U
U
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006822:Hybrid Cells; D020748:Mibefradil / Q000494:pharmacology; D051379:Mice; D009543:Nifedipine / Q000031:analogs & derivatives / Q000494:pharmacology*; D015737:Nisoldipine / Q000494:pharmacology; D051381:Rats; D014407:Tumor Cells, Cultured
C438212:1,4-dihydro-2,6-dimethyl--4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid ethyl-1-methylethyl ester; D002121:Calcium Channel Blockers; D015220:Calcium Channels; C033710:1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester; D020748:Mibefradil; D015737:Nisoldipine; D009543:Nifedipine