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

• Published in: Pharmacological research 2001-08, Vol.44 (2), p.113-116
• Main Authors: Himmel, Herbert M., Stengel, Wolfgang, Ravens, Ursula
• Format: Article
• Language: English
• Subjects: Animals; Calcium Channel Blockers - pharmacology; Calcium Channels - drug effects; Calcium Channels - physiology; Dose-Response Relationship, Drug; Electrophysiology; Hybrid Cells; Mibefradil - pharmacology; Mice; neuroblastoma–glioma hybrid cells, Ca2+channels, high-voltage activated, low-voltage activated,[formula omitted] -type, [formula omitted] -type, [formula omitted] -type, dihydropyridine derivatives; Nifedipine - analogs & derivatives; Nifedipine - pharmacology; Nisoldipine - pharmacology; Rats; Tumor Cells, Cultured
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1006/phrs.2001.0836

Beneficial therapeutic effects of dihydropyridine derivatives in cardiovascular 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 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 Ba2+currents mediated by low-(LVACC)vs high-voltage activated Ca2+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 μ M. The order of potency for blockade of HVACC was Bay E5759 (IC50: 0.4 nM) > Bay A4339 (2.5 nM) ∼= nisoldipine (4 nM) ⪢ mibefradil (3.8 μ M). Thus Bay E5759 and Bay A4339 are highly potent and selective blockers of HVACC, presumably L-type Ca2+channels.