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-benzodiaze pine (BDZ) and azirino[1,2-d][1,4]benzodiazepine (ABDZ) derivatives we re studied after intraperitoneal administration in DBA/2 mice, a strai n genetically susceptible to sound induced seizures. 2. The anticonvul sant effects were evaluated on seizures evoked by means of auditory st imulation (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 > A BDZ6 > ABDZ2. 4. The impairment of locomotor performance following int raperitoneal (IF) administration of the aforementioned derivatives was also evaluated by means of rotarod test. The rank order of potency fo r impairment of coordinated motor movements was pinazepam > flunitraze pam > diazepam > ABDZ5 > prazepam > halazepam > ABDZ4 > ABDZ3 > ABDZ1 > camazepam > ABDZ2 = ABDZ6. 5. A hypothermic activity was observed af ter the highest doses of the benzodiazepines studied. 6. The potency o f various 1,4-benzodiazepines and azirino[1,2-d][1,4]benzodiazepines a s inhibitors of specific [H-3]flumazenil binding to membranes from cer ebellum or cortex was evaluated. In general, they inhibited [H-3]fluma zenil binding at the micromolar range. However, some ABDZ derivatives, although active as anticonvulsants, failed to displace [H-3]flumazeni l. 7. The azirino[1,2-d][1,4]benzodiazepine derivatives are more lipop hilic than the related benzodiazepines, but the different degree of an ticonvulsant activity and impairment of coordinated motor movements ca nnot be directly related to the lipophilicity of the compounds studied . 8. The pharmacologic actions of ABDZ4 and ABDZ5, which appeared as t he most potent anticonvulsants of the azirino[1,2-d][1,4]benzodiazepin e 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 als o evaluated against seizures induced by the two beta-carbolines, methy l beta-carboline-3-carboxylate (beta-CCM) and 6,7-dimethoxy-4-ethyl-be ta-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.