Interaction of the novel anticonvulsant, BIA 2-093, with voltage-gated sodium channels: Comparison with carbamazepine

Purpose: BIA 2-093 [(S)-(-)- 10-acetoxy-10,11-dihydro-54-dibenz/b,f/azepine -5-carboxamide is endowed with an anticonvulsant potency similar to that of carbamazepine (CBZ), but produces less cognitive and motor impairment. Thi s study evaluated whether voltage-gated sodium channels (VGSCs) are a prima ry locus for the action of BIA 2-093. Methods: We used the whole-cell voltage-clamp technique in the mouse neurob lastoma cell line N1E-115 to investigate the effects of BIA 2-093 and CBZ o n VGSCs. displacement of [H-3]-batrachotoxinin A 20-alpha -benzoate (H-3]-B TX), and [H-3] saxitoxin to define their relative potency to bind to rat br ain sodium channels, and inhibition of uptake of Na-22 by rat brain cortica l synaptosomes stimulated by veratridine as a measure of sodium entry. Results: The inhibitory potencies of BIA 2-093 and CBZ increased as the hol ding potential was made less negative (-100. -90. -80, and -70 mV) with med ian inhibitory concentration (IC50) values (in muM) of, respectively, 4,337 , 618, 238, and 139 for BIA 2-093, and 1,506, 594. 194, and 101 for CBZ. BI A 2-093 displayed a similar potency in displacing [3H]-BTX (IC50 values, 22 2 vs. 361 muM; P > 0.05) and inhibiting the uptake of Na-22 (IC50 values, 3 6 vs. 138 muM; p > 0.05). Both drugs failed to displace [H-3]-saxitoxin in concentrations up to 300 muM. Conclusions: BIA 2-093, like CBZ, inhibits sodium currents in a voltage-dep endent way by an interaction predominantly with the inactivated state of th e channel and interacts with neurotoxin receptor site 2, but not with recep tor site 1. BIA 2-093 displayed a potency blocking VGSCs similar to that of CBZ.