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

J Med Chem. 1986 Oct;29(10):1996-9. doi: 10.1021/jm00160a032.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 4-Butyrolactone / analogs & derivatives
  • 4-Butyrolactone / chemical synthesis
  • 4-Butyrolactone / pharmacology*
  • Animals
  • Anticonvulsants / chemical synthesis
  • Anticonvulsants / pharmacology*
  • Convulsants / chemical synthesis
  • Convulsants / pharmacology*
  • Female
  • Furans / pharmacology*
  • Mice
  • Structure-Activity Relationship

Substances

  • Anticonvulsants
  • Convulsants
  • Furans
  • 4-Butyrolactone