Structure activity relationships of selected benzodiazepines as anticonvulsants to local anesthetics

Diazepam, oxazepam, N-methyloxazepam, nitrazepam and N-desmethyldiazepam prevented seizures in mice produced by lidocaine, mepivacaine, and prilocaine, and in rats by lidocaine when administered IP five minutes before IP local anesthetic. ED50 values for antagonism of lidocaine tremors ranged from 0.7 to 5.2 mg/kg for N-methyloxazepam and N-desmethyldiazepam respectively in mice, and 0.08 to 0.54 mg/kg for N-desmethyldiazepam and oxazepam respectively, and for antagonism of prilocaine convulsions, 0.2 to 0.6 mg/kg for N-methyloxazepam and N-desmethyldiazepam respectively. All compounds tested terminated ongoing lidocaine tremors when injected IV in mice with ED50 values ranging from 1.7 x 10(-3) to 3.0 x 10(-3) mg/kg for N-desmethyldiazepam and N-methyloxazepam respectively, N-methyloxazepam was significantly more potent after IP injection than nitrazepam, oxazepam and N-desmethyldiazepam against lidocaine in mice and more potent than N-desmethyldiazepam and oxazepam against mepivacaine; it was more potent than diazepam and oxazepam against lidocaine in rats. N-desmethyldiazepam was most potent against lidocaine in rats and lest potent in mice. There were no significant differences in ED50 values preventing prilocaine convulsions in mice or after IV injection to terminate ongoing lidocaine seizures. The presence of a methyl and hydroxyl group at position N-1 and C-3 respectively (N-methyloxazepam) was apparently responsible for the higher potency relative to some of the other compounds in preventing lidocaine and mepivacaine tremors in mice and lidocaine tremors in rats. It is concluded however that the magnitudes of differences in potencies of the compounds in antagonizing local anesthetic seizures in mice and rats were not so large as to prefer any single agent over diazepam.