Azirino[1,2-d][1,4]benzodiazepine derivatives and related 1,4-benzodiazepines as anticonvulsant agents in DBA/2 mice

1. The behavioral and anticonvulsant effects of several 1,4-benzodiazepine (BDZ) and azirino[1,2-d][1,4]benzodiazepine (ABDZ) derivatives were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound induced seizures. 2. 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. 3. The 1,4-benzodiazepines were generally more potent than the related azirino[1,2-d][1,4]benzodiazepine derivatives which, however, showed a remarkable anticonvulsant activity. The rank order of potency for anticonvulsant activity was flunitrazepam > diazepam > pinazepam > ABDZ5 > ABDZ4 > prazepam > halazepam > ABDZ1 > ABDZ3 > camazepam > ABDZ6 > ABDZ2. 4. The impairment of locomotor performance following intraperitoneal (IF) administration of the aforementioned derivatives was also evaluated by means of rotarod test. The rank order of potency for impairment of coordinated motor movements was pinazepam > flunitrazepam > diazepam > ABDZ5 > prazepam > halazepam > ABDZ4 > ABDZ3 > ABDZ1 > camazepam > ABDZ2 = ABDZ6. 5. A hypothermic activity was observed after the highest doses of the benzodiazepines studied. 6. The potency of various 1,4-benzodiazepines and azirino[1,2-d][1,4]benzodiazepines as inhibitors of specific [H-3]flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, they inhibited [H-3]flumazenil binding at the micromolar range. However, some ABDZ derivatives, although active as anticonvulsants, failed to displace [H-3]flumazenil. 7. The azirino[1,2-d][1,4]benzodiazepine derivatives are more lipophilic than the related benzodiazepines, but the different degree of anticonvulsant activity and impairment of coordinated motor movements cannot be directly related to the lipophilicity of the compounds studied. 8. The pharmacologic actions of ABDZ4 and ABDZ5, which appeared as the most potent anticonvulsants of the azirino[1,2-d][1,4]benzodiazepine derivatives, were significantly reduced by treatment with flumazenil (8.24 mu mol/kg IF) suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. 9. The anticonvulsant activity of ABDZ4 and ABDZ5 was also evaluated against seizures induced by the two beta-carbolines, methyl beta-carboline-3-carboxylate (beta-CCM) and methyl6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), in DBA/2 mice. Both ABDZ4 and ABDZ5 gave better protection against the seizures induced by beta-CCM than DMCM, suggesting a preferential action on BDZ1 receptors. Copyright (C) 1996 Elsevier Science Inc.