Comparison of the anticonvulsant effects of two novel GABA uptake inhibitors and diazepam in amygdaloid kindled rats

Summary

Two novel, specific inhibitors of GABA uptake, namely SKF 89976-A (N-[4,4-diphenyl-3-butenyl]-nipecotic acid) and SKF 100330-A (N-[4,4-diphenyl-3-butenyl]-guvacine) were tested for anticonvulsant effects in amygdaloid kindled female rats. The anticonvulsant effectiveness of the compounds was compared with that of diazepam. SKF 89976-A and SKF 100330-A produced dosedependent anticonvulsant effects on all seizure parameters measured in fully kindled rats, i.e. they inhibited seizure severity, increased seizure latency, and decreased the duration of motor seizures and EEG afterdischarges. ED 50s for inhibition of seizure severity were 4.6 and 15.1 mg/kg (0.014 and 0.045 mmol/kg) i.p. for SKF 100330-A and SKF 89976-A, respectively. For comparison, the ED 50 of diazepam was 1.9 mg/kg (0.0067 mmol/kg) i.p. Observation of behaviour indicated that the novel GABA uptake blockers exerted no side-effects in anticonvulsant doses, whereas diazepam produced sedative effects at all active dosage levels. The data demonstrate that SKF 100330-A and SKF 89976-A are potent, non-sedative anticonvulsant drugs in the kindling model of epilepsy, and these compounds thus may deserve interest as potential antiepileptic drugs with a very selective mechanism of action.