Comparison of epileptogenic properties of unsubstituted and β-alkyl-substitued γ-butyrolactones

W. E. Klunk, D. F. Covey, J. A. Ferrendelli

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Abstract

β-Ethyl-β-methyl and β,β-dimethyl-γ-butyrolactones (β-EMGBL, β-DMGBL), their corresponding hydroxy acids (β-EMGHB, β-DMGHB), and rigid cis and trans analogues of γ-hydroxybutyrate were synthesized. These compounds were tested in mice and guinea pigs in vivo and in incubated guinea pig hippocampal slices, and their effects were compared with those of unsubstituted γ-butyrolactone (GBL) and γ-hydroxybutyrate (GHB). β-EMGBL produced convulsive seizures and epileptiform electroencephalographic (EEG) discharges consisting of spike and polyspike activity. β-DMGBL, β-EMGHB, and the rigid cis analogue of GHB produced behavioral and EEG effects similar to that of β-EMGBL, but all were less potent. In contrast, GBL, GHB, and the rigid trans analogue of GHB caused nonconvulsive seizures and epileptiform EEG discharges consisting mainly of irregular slow-wave activity. Neuronal activity in hippocampal slices was markedly activated by β-EMGBL, but β-EMGHB, GBL, and GHB had little or no effect. Seizures produced by both the substitued and unsubstituted GBLs were suppressed by ethosuximide but not by phenytoin. The results of this study demonstrate that β-alkyl-substituted GBLs are convulsant agents and the effects of these compounds are different from those of GHB or GBL. The results also suggest that the β-substituted compounds are active in a lactone form whereas the unsubstituted compounds are active as hydroxy acids. Thus the β-substituted and the unsubstituted compounds probably act at different sites and have different mechanisms of action.

Original languageEnglish
Pages (from-to)431-437
Number of pages7
JournalMolecular pharmacology
Volume22
Issue number2
StatePublished - Jan 1 1982

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