Evaluation of motor toxicity and anticonvulsant efficacy of barbiturates and benzodiazepines in a bicyclophosphate seizure model in mice

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1. 4-Alkyl derivatives of 2,6,7-trioxa-l-phosphabicyclo [2.2.2] octane-I-oxide [Bicyclophosphates (BP)] are highly toxic convulsants and potent GABAA receptor antagonists. 2. The effects of various clinical used anticonvulsant drugs, barbiturates and benzodiazepines, on motor performance and 4-isopropylbicyclophosphate (IPBP), a homologue of BP, induced myoclonic and generalized tonic-clonic seizures were investigated in mice. 3. The anticonvulsant drugs were IP administered 30 min. prior to the inverted screen test, a measure of minimal neurological deficit, and were then challenged with a 97% convulsant dose of IPBP (0.15 mg/kg, SC). 4. The results show that: 1) benzodiazepines are more likely to have favorable motor toxicity and anticonvulsant profiles than barbiturates. 2) Various doses of these drugs that did not significantly cause motor impairment increase the mean latencies to myoclonic and generalized tonic-clonic seizures. 3) The increase in anticonvulsant activity is associated with a comparable increase in motor impairment. 4) Only 45-0088-S, an open-ring derivative of 1,4-benzodiazepines, and clonazepam have protective indices of more than 5, a satisfactory margin of safety. 5. The potential use of 45-0088-S and clonazepam in the treatment of BP-induced seizures should be explored further.