Anticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives

A. series of esters of the major metabolite of oxcarbazepine (2), 10,11-dih ydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, were synthesized and e valuated for their anticonvulsant and brain sodium channel-blocking propert ies. The compounds were assayed intraperitoneally and per os in rats agains t seizures induced by maximal electroshock (MES). Neurologic deficit was ev aluated by the rotarod test. The enantiomeric acetates (R)-11 and (S)-12 we re the most active of the series against MES-induced seizures with oral ED5 0 values at t(max) of 10.9 +/- 2.3 and 4.7 +/- 9 mg/kg, respectively. After intraperitoneal administration, carbamazepine (1) behaved more potently th an 2 and all other new dibenz[b,f]azepine-5-carboxamide derivatives in the MES test; compounds 2 and 12 were equally potent. In the rotarod test, low doses of 1. produced considerable motor impairment, which did not occur wit h 2, enantiomeric alcohols (S)-6;, (R)-7, and racemic alcohol, or racemic a cetate 10 or (R)-11. The potencies of the racemic and enantiomerically pure alcohols 8, (S)-6, and (R)-7 derived from 2 in the MES and rotarod test we re found to be similar between them, and consequently they exhibit similar protective index values. All three forms of the alcohol and their correspon ding acetates (pairs 8 & 10, 6 & 12, and 7 & 11) were found to differ in th e MES or rotarod tests; the ED50 value for (S)-6 against MES-induced seizur es was nearly 3-fold that for (S)-12. The protective index also differed ma rkedly between all stereoisomers of the alcohol and their corresponding ace tates, most pronouncedly for compound (S)-12 which attained the highest val ue (12.5) among all compounds tested. Blockade of voltage-sensitive sodium channels was studied by investigating [H-3]-batrachotoxinin A 20-alpha-benz oate ([H-3]BTX) binding. Acetates (R)-11 and (S)-12 were more potent than t he standards 1 and-2 at inhibiting the binding of [H-3]BTX to sodium channe ls and the influx: of Na-22(+) into rat brain synaptosomes. It is concluded that acetates (R)-11 and (5)-12 are not simple metabolic precursors of alc ohols (R)-7 and (S)-6 in rodents but that they possess anticonvulsant and s odium channel-blocking properties in their own right.