Alkyl-Substituted Thiolo-, Thiono-, and Dithio-γ-butyrolactones: New Classes of Convulsant and Anticonvulsant Agents

Jeffrey A. Levine, James A. Ferrendelli, Douglas F. Covey

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

A series of sulfur-containing congeners have been prepared from α-ethyl-α-methyl-γ-butyrolactone, β-ethyl-β-methyl-7-butyrolactone, and α,α,β,β-tetramethyl-7-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 β-substituted and α,β-substituted congeners were potent convulsants that caused generalized clonic and tonic seizures in mice. The a-substituted congeners were effective in inhibiting pentylenetetrazole-induced seizures in mice. α-Ethyl-α-methylthiolo-γ-butyrolactone showed an increase in potency over the congeneric α-ethyl-α-methyl-γ-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.

Original languageEnglish
Pages (from-to)1996-1999
Number of pages4
JournalJournal of Medicinal Chemistry
Volume29
Issue number10
DOIs
StatePublished - 1986

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