Inhibition of glutamate release by BIA 2-093 and BIA 2-024, two novel derivatives of carbamazepine, due to blockade of sodium but not calcium channels

We investigated the mechanism(s) of action of two new putative antiepilepti c drugs (AEDs), (S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-ca rboxamide (BIA 2-093) and 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepi ne-5-carboxamide (BIA 2-024). by comparing their effects on the release of endogenous glutamate in hippocampal synaptosomes. with those of carbamazepi ne (CBZ) and oxcarbazepine (OXC). The AEDs inhibited the release of glutama te evoked by 4-aminopyridine (4-AP) or veratridine in a concentration-depen dent manner, being CBZ more potent than the other AEDs. Using conditions of stimulation (30 mM KCl), where Na+ channels are inactivated, the AEDs did not inhibit either the Ca2+-dependent or -independent release of glutamate. The results indicate that BIA 2-093 and BIA 2-024 have sodium channel-bloc king properties, but CBZ and OXC are more potent than the new AEDs. Moreove r, the present data also indicate that Ca2+ channels coupled to the exocyto tic release of glutamate and the activity of the glutamate transporter were not affected by the AEDs. (C) 2001 Elsevier Science Inc. All rights reserv ed.