A series of gamma-butyrolactones and gamma-thiobutyrolactones possessing a variety of alkyl groups and alkyl-substitution patterns was prepared and evaluated for anticonvulsant and convulsant activity. Behavioral studies performed on these compounds suggest that maximal anticonvulsant activity (against maximal electroshock and pentylenetetrazol) results when three or four carbon atoms are present at the alpha-position. For convulsant potency, a similar dependence on the size of the alkyl chain at the beta-position was observed. Additional gamma-dimethyl groups were found to increase the convulsant potency of a beta-substituted compound and to cause an alpha-substituted anticonvulsant to become a convulsant. In general, sulfur for oxygen heteroatom substitution in the alpha-substituted lactones resulted in improved anticonvulsant potency and spectrum of activity. Binding of these compounds to the picrotoxin site of the GABA receptor complex was demonstrated with a [35S]-tert-butylbicyclophosphorothionate radioligand binding assay. Measurements of brain concentrations for selected compounds supports a hypothesis that correlates binding to the picrotoxin site with the pharmacological effects of these compounds.