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

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.

• Authors: J A Levine, J A Ferrendelli, D F Covey
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 29 Issue 10 Pg. 1996-9 (Oct 1986) ISSN: 0022-2623 [Print] United States
• PMID: 3761317 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anticonvulsants
• Convulsants
• Furans
• 4-Butyrolactone

Topics

• 4-Butyrolactone (analogs & derivatives, chemical synthesis, pharmacology)
• Animals
• Anticonvulsants (chemical synthesis, pharmacology)
• Convulsants (chemical synthesis, pharmacology)
• Female
• Furans (pharmacology)
• Mice
• Structure-Activity Relationship