CA2-40116 AND CGP-43487, IN MICE( CHANNEL BLOCKADE AND THE ANTIELECTROSHOCK ACTIVITY OF NMDA RECEPTOR ANTAGONISTS, CGP)

Nicardipine, nifedipine and flunarizine showed anticonvulsive activity (reflected by significant elevations of the seizure threshold for ton ic hindlimb extension) in doses of 20, 20 and 15 mg/kg, respectively. In combination studies, CGP 40116 [D-(E)-2-amino-4-methyl5-phosphono-3 -pentenoic acid] or its methyl ester derivative (CGP 43487) was admini stered in a constant dose of 0.25 and 3.5 mg/kg, respectively. At thes e doses both competitive NMDA receptor antagonists were able to elevat e significantly the convulsive threshold. Nicardipine, nifedipine, and flunarizine were administered at maximal doses (or lower) not affecti ng the convulsive threshold(15, 15 and 10 mg/kg, respectively). The pr otective activity of CGP 40116 and CGP 43487 was dose dependently pote ntiated by all three Ca2+ channel inhibitors. The combined treatment c aused motor impairments (evaluated in the chimney test) and long-term memory deficits (measured in the passive avoidance task) similar to th ese produced by CGP 40116 or CGP 43487 alone. Our results indicate tha t nicardipine, nifedipine and flunarizine significantly potentiate the protective activity, but not the adverse effects, of CGP 40116 and CG P 43487 in mice.