The
anticonvulsant properties of several
1,4-benzodiazepine and azirino[1,2-d][1,4]
benzodiazepine (ABDZ) derivatives were studied after intraperitoneal (IP) administration in DBA/2 mice (a strain genetically susceptible to sound-induced
seizures) and in Swiss mice. The
anticonvulsant effects were evaluated on
seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a hemispheric Perspex dome or on
seizures induced by administration of
pentylenetetrazole. The 1,4-benzodiazepines were generally more potent than the related ABDZ derivatives. The rank order of potency for
anticonvulsant activity was
flunitrazepam >
diazepam >
pinazepam > ABDZ5 > ABDZ4 >
prazepam >
halazepam > ABDZ1 > ABDZ3 >
camazepam > ABDZ6 > ABDZ2. The impairment of locomotor performance following IP administration of these derivatives was also evaluated by means of the 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. The potency of various 1,4-benzodiazepines and ABDZs as inhibitors of specific [3H]
flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, ABDZs were active as
anticonvulsants and inhibited [3H]
flumazenil binding in the micromolar range. Radioligand binding studies carried out in stable cell lines demonstrated that none of the ABDZs tested showed a particular subtype specificity. The pharmacological actions of ABDZ4 and ABDZ5, which appeared to be the most potent ABDZs as
anticonvulsants, were significantly reduced by treatment with
flumazenil (8.24 mumol/kg IP), suggesting a clear involvement of
benzodiazepine mechanisms in the
anticonvulsant activity of these compounds or their metabolites. The
anticonvulsant activity of ABDZ4 and ABDZ5 was also evaluated against
seizures induced in DBA/2 mice by two
beta-carbolines: methyl-beta-carboline-3-carboxylate (
beta-CCM) and methyl-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, suggesting a preferential action on the
benzodiazepine receptor subtype BDZ1.