Several diphenylmethylpiperazine derivatives are potential therapeutic agents for prevention of ischemic injuries in the heart and brain, because of their ability to block Ca2+ currents and their antioxidant activity. In this study, the current lead compound, U-92032 ((7-((bis-4-fluorophenyl)methyl)-1-piperazinyl)-2-(2-hydroxyethylamin o)- 4-(1-methylethyl)-2,4,6-cycloheptatrien-1-one), has been compared with flunarizine and nifedipine (well-known T- and L-type Ca2+ channel antagonists, respectively) for their effects on Ca2+ channels in a mouse neuronal cell line, N1E-115 cells, and their ability to preserve the phenomenon of long-term potentiation and to improve neurological symptoms in gerbil ischemic models. U-92032, like flunarizine, blocked transient Ba2+ currents (IBa) through T-type Ca2+ channels with no effect on nifedipine-sensitive non-inactivating currents. Transient IBa was reduced by U-92032 at a constant rate, the magnitude of which depended on the drug concentration, probably because of a time-dependent accumulation of the lipophilic drug in the membrane phase. For instance, the drug at 6 microM reduced IBa by 21% per min and abolished it in less than 5 min, about 3 times faster than flunarizine at the same concentration. Otherwise, U-92032 behaved like flunarizine, showing a use-dependent block without noticeable effects on the current-voltage relationship for transient IBa. Oral administration of U-92032 (1 and 25 mg/kg) or flunarizine (25 mg/kg), but not nifedipine (50 mg/kg), to gerbils 1 h prior to bilateral carotid artery occlusion, preserved long-term potentiation in hippocampal CA1 neurons, which were largely abolished by ischemia without the drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)