ANTICONVULSANT PROPERTIES OF SOME BENZODIAZEPINES

¹ Departments of Pharmacology, University of Utah College of Pharmacy and College of Medicine, Salt Lake City, Utah

The anticonvulsant potencies (ED50) of chlordiazepoxide (Librium), diazepam (Valium) and 7 experimental benzodiazepines were determined in mice by the following 3 tests: maximal electroshock seizure pattern (MES) test, low-frequency electroshock seizure threshold (l.f. EST) test and pentylenetetrazol (Metrazol) seizure threshold (s.c. Met) test. In addition, the dose of eachdrug which produced overt evidence of neurotoxicity in 50% of animals (TD50) was determined andprotective indices (PI = TD50/ED50) were calculated. Three of the more potent agents (chlordiazepoxide; compound 5, 7-nitro-5-(2-chlorophenyl)-3H-1,4-benzodiazepine-2(1H)-one; and compound 7, 7-nitro-5-(2-fluoromethylphenyl)-3H-1,4-benzodiazepine-2(1H)-one) were compared with trimethadione for ability to abolish the tonic extensor component of maximal pentylenetetrazol seizures(MMS test). Intravenously administered chlordiazepoxide, compound 5 and trimethadione also werecompared for ability to elevate by 100% the intravenous pentylenetetrazol seizure threshold. Finally, the effects of chlordiazepoxide and compound 5 on synaptic transmission were investigated in unanesthetized spinal cats. On the basis of the results obtained, the following conclusions appear justified: 1) Except for compounds 5 and 7 by the MES test, all 9 benzodiazepines tested are effective by all 3 tests; however, compound 6 (7-nitro-1-methyl-5-(2-fluorphenyl)-3H-1,4-benzodiazepine-2(1H)-one) was effective by the l.f. EST test only in a dose greatly in exces of the TD50. Compounds 5 and 7 were ineffective by the MES test, but were remarkably active by the l.f. EST, s.c. Met and MMS tests. 2) Compound 1 (7-chloro-4,5-dihydro-5-phenyl-3H-1,4-benzodiazepine-2(1H)-one) has the highest PI by the MES test (8.4) and compound 5 has the highest PI by the l.f. EST (3081) and s.c. Met (7983) tests. 3) Compound 5, administered intravenously, was determined to be 4750 times more potent than trimethadione in elevating by 100% the threshold for seizures induced by the intravenous administration of pentylenetetrazol. 4) Although chlordiazepoxide and compound 5 had no significant effect on transmission of isolated impulses in monosynaptic and polysynaptic pathways or on posttetanic potentiation in unanesthetized spinal cats, both drugs decreased the response to repetitive stimulation. This depressant effect was abolished with appropriate doses of pentylenetetrazol. In view of the favorable profile of anticonvulsant action of compound 1 and the unique antipentylenetetrazol activity of compound 5, these, and possibly other henzodiazepines included in this study, appear worthy of cautious clinical trial in epilepsy.

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