1, 4-Benzodiazepine derivatives as anticonvulsant agents in DBA/2 mice

The behavioural and anticonvulsant effects of 10 1,4-benzodiazepine derivatives were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a perspex dome. The rank order of potency for anticonvulsant activity was alprazolam > clonazepam > flunitrazepam > diazepam > pinazepam > desmethyldiazepam > oxazepam > prazepam > halazepam > camazepam. The impairment of locomotor performance following IP administration of the above reported derivatives was also evaluated by means of the rotarod test. Hypothermic activity was observed after the highest doses of the benzodiazepines studied. The potency of various 1,4-benzodiazepines as inhibitors of specific [3H] flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, 1,4-benzodiazepines were active as anticonvulsants at micromolar range and inhibited [3H] flumazenil binding at nanomolar range. The different degree of anticonvulsant activity and impairment of coordinated motor movements cannot be directly related to the benzodiazepine binding affinity or to the lipophilicity of the compounds studied