Two novel 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 genetically seizure-prone gerbils. Both compounds proved able to block major (generalized tonic-clonic) seizures initiated in gerbils by air blast stimulation. The respective anticonvulsant ED50s for SKF 100330-A and SKF 89976-A were 1.6 and 4.1 mg/kg i.p., respectively. Comparison with other GABA uptake inhibitors, namely ethyl and methyl esters of (-)- and (+)-nipecotic acid and (±)-cis-4-hydroxynipecotic acid, showed that the novel uptake inhibitors were considerably more potent. Similarly, comparison with common antiepileptic drugs demonstrated that SKF 100330-A and SKF 89976-A were more potent than phenobarbital and valproic acid to block seizures in gerbils. Only benzodiazepines surpassed these GABA uptake inhibitors in anticonvulsant potency. Observation of behaviour indicated that the novel compounds exerted no side-effects in anticonvulsant doses. These data indicate that SKF 100330-A and SKF 89976-A deserve interest as potential antiepileptic drugs with a very selective mechanism of action. © 1985.
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