Alkyl-substituted thiolo-, thiono-, and dithio-gamma-butyrolactones: new classes of convulsant and anticonvulsant agents.
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.
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology*; D003292:Convulsants / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D005663:Furans / Q000494:pharmacology*; D051379:Mice; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D003292:Convulsants; D005663:Furans; D015107:4-Butyrolactone