TY - JOUR
T1 - Alkyl-Substituted Thiolo-, Thiono-, and Dithio-γ-butyrolactones
T2 - New Classes of Convulsant and Anticonvulsant Agents
AU - Levine, Jeffrey A.
AU - Ferrendelli, James A.
AU - Covey, Douglas F.
PY - 1986
Y1 - 1986
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0022532847&partnerID=8YFLogxK
U2 - 10.1021/jm00160a032
DO - 10.1021/jm00160a032
M3 - Article
C2 - 3761317
AN - SCOPUS:0022532847
SN - 0022-2623
VL - 29
SP - 1996
EP - 1999
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 10
ER -