STRUCTURE-ACTIVITY STUDIES OF FLUOROALKYL-SUBSTITUTED GAMMA-BUTYROLACTONE AND GAMMA-THIOBUTYROLACTONE MODULATORS OF GABA(A) RECEPTOR FUNCTION

Dihydro-2(3H)-furanones (gamma-butyrolactones) and dihydro-2(3H)-thiop henones (gamma-thiobutyrolactones) containing fluoroalkyl groups at po sitions C-3, C-4, and C-5 of the heterocyclic rings were prepared, The anticonvulsant/convulsant activities of the compounds were evaluated in mice, Brain concentrations of the compounds were determined and the effects of the compounds on [S-35]-tert-butylbicyclophosphorothionate ([S-35]TBPS) binding to the picrotoxin site on GABA(A) receptors were investigated. The effects of the compounds on GABA(A) receptor functi on were studied using electrophysiological methods and cultured rat hi ppocampal neurons. Fluorination at C-3 results in either subtle or pro nounced effects on the pharmacological activity of the compounds. When hydrogens are replaced with fluorines at the methylene carbon of an e thyl group, as in (1,1-difluoroethyl)dihydro-3-methyl-2(3H)-furanone ( 1), the anticonvulsant actions of the compound are not much changed fr om those found for the corresponding alkyl-substituted analogue. In ma rked contrast, fluorination at the methyl carbon of the ethyl group, a s in o-3-methyl-3-(2,2,2-trifluoroethyl)-2(3H)-furanone (3), produces a compound having convulsant activity, This convulsant activity seems to be due to an increased affinity of the compound for the picrotoxin site on GABA(A) receptors caused by an interaction that involves the t rifluoromethyl group. Results obtained with gamma-butyrolactones conta ining either a 3-(1-trifluoromethyl)ethyl or a 3-(1-methyl-1-trifluoro methyl)ethyl substitutent indicate that the interactions of the triflu oromethyl group with the picrotoxin binding site are subject to both s tereochemical and steric constraints. Sulfur for oxygen heteroatom sub stitution, as in the corresponding gamma-thiobutyrolaclones, affects t he type (competitive, noncompetitive, etc.) of binding interactions th at these compounds have with the picrotoxin site in a complex manner. Fluorination of alkyl groups at the C-4 and C-5 positions of gamma-but yrolactones having convulsant activity increases convulsant potency. ( C) 1998 Elsevier Science Ltd. All rights reserved.