ANTICONVULSANT ACTIVITY OF AZIRINO[1,2-D][1,4]BENZODIAZEPINES AND RELATED 1,4-BENZODIAZEPINES IN MICE

The anticonvulsant properties of several 1,4-benzodiazepine and azirin o[1,2-d][1,4]benzodiazepine (ABDZ) derivatives were studied after intr aperitoneal (IF) administration in DBA/2 mice (a strain genetically su sceptible to sound-induced seizures) and in Swiss mice. 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 hemisph eric Perspex dome or on seizures induced by administration of pentylen etetrazole. The 1,4-benzodiazepines were generally more potent than th e related ABDZ derivatives; The rank order of potency for anticonvulsa nt activity was flunitrazepam > diazepam > pinazepam > ABDZ5 > ABDZ4 > prazepam > halazepam > ABDZ1 > ABDZ3 > camazepam > ABDZ6 > ABDZ2. The impairment of locomotor performance following IP administration of th ese derivatives was also evaluated by means of the rotarod test. The r ank order of potency for impairment of coordinated motor movements was pinazepam > flunitrazepam > diazepam > ABDZ5 > prazepam > halazepam > ABDZ4 > ABDZ3 > ABDZ1 > camazepam, ABDZ2 = ABDZ6. The potency of Vari ous 1,4-benzodiazepines and ABDZs as inhibitors of specific [H-3]fluma zenil binding to membranes from cerebellum or cortex was evaluated. In general, ABDZs were active as anticonvulsants and inhibited [H-3]flum azenil binding in the micromolar range. Radioligand binding studies ca rried out in stable cell lines demonstrated that none of the ABDZs tes ted showed a particular subtype specificity. The pharmacological actio ns of ABDZ4 and ABDZ5, which appeared to be the most potent ABDZs as a nticonvulsants, were significantly reduced by treatment with flumazeni l (8.24 mu mol/kg IF), suggesting a clear involvement of benzodiazepin e mechanisms in the anticonvulsant activity of these compounds or thei r metabolites. The anticonvulsant activity of ABDZ4 and ABDZ5 was also evaluated against seizures induced in DBA/2 mice by two beta-carbolin es: methyl-beta-carboline-3-carboxylate (beta-CCM) and 6,6-dimethoxy-4 -ethyl-beta-carboline-3-carboxylate (DMCM). Both ABDZ4 and ABDZ5 give better protection against seizures induced by beta-CCM than DMCM, sugg esting a preferential action on the benzodiazepine receptor subtype BD Z1. (C) 1997 Elsevier Science Inc.