title: Anticonvulsant activity of azirino[1,2-d][1,4]benzodiazepines and related 1,4-benzodiazepines in mice.
abstract: 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.
authors.affiliation: Institute of Pharmacology, School of Medicine, University of Reggio Calabria and Messina, Catanzaro, Italy. desarro@thebrain.net
authors.forename: G
authors.initials: G
authors.lastname: De Sarro
authors.forename: A
authors.initials: A
authors.lastname: Chimirri
authors.forename: R
authors.initials: R
authors.lastname: McKernan
authors.forename: K
authors.initials: K
authors.lastname: Quirk
authors.forename: P
authors.initials: P
authors.lastname: Giusti
authors.forename: A
authors.initials: A
authors.lastname: De Sarro
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002243:Carbolines; D002460:Cell Line; D003292:Convulsants / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D008297:Male; D008566:Membranes / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D009068:Movement / Q000187:drug effects; D010433:Pentylenetetrazole; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control
chemical_list: D000927:Anticonvulsants; D002243:Carbolines; D003292:Convulsants; D018757:GABA Modulators; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D005442:Flumazenil; C036150:beta-carboline-3-carboxylic acid methyl ester; D010433:Pentylenetetrazole