Alkyl-substituted thiolo-, thiono-, and dithio-.gamma.-butyrolactones: new classes of convulsant and anticonvulsant agents

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Abstract
A series of sulfur-containing congeners have been prepared from .alpha.-ethyl-.alpha.-methyl-.gamma.-butyrolactone, .beta.-ethyl-.beta.-methyl-.gamma.-butyrolactone, and .alpha.,.alpha.,.beta.,.beta.-tetramethyl-.gamma.-butyrolactone as potential neuropharmacologic agents. The lactones were treated with benzyl mercaptide anion to form 4-(benzylthio)butyric acid, which, on treatment with trifluoroacetic acid, cyclized to yield thiololactones. The thiono- and dithiolactones were prepared by treating the corresponding lactones either with Lawesson''s reagent or with phosphorus pentasulfide, respectively. As had been observed previously for the lactones, the .beta.-substituted and .alpha.,.beta.-substituted congeners were potent convulsants that caused generalized clonic and tonic seizures in mice. The .alpha.-substituted congeners were effective in inhibiting pentylenetetrazole-induced seizures in mice. .alpha.-Ethyl-.alpha.-methylthiolo-.gamma.-butyrolactone showed an increase in potency over the congeneric .alpha.-ethyl-.alpha.-methyl-.gamma.-butyrolactone and, additionally, was effective against maximal electroshock seizures. In no cases was a convulsant converted to an anticonvulsant or vice versa by sulfur-for-oxygen substitution.