Structure-activity studies of fluoroalkyl-substituted γ-butyrolactone and γ-thiobutyrolactone modulators of GABA(A) receptor function

Daniel J. Canney, Hwang Fun Lu, Ann C. McKeon, Kong Woo Yoon, Kun Xu, Katherine D. Holland, Steven M. Rothman, James A. Ferrendelli, Douglas F. Covey

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Dihydro-2(3H)-furanones (γ-butyrolactones) and dihydro-2(3H)-thiophenones (γ-thiobutyrolactones) containing fluoroalkyl groups at positions 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 [35S]-tert-butylbicyclophosphorothionate ([35S]TBPS) binding to the picrotoxin site on GABA(A) receptors were investigated. The effects of the compounds on GABA(A) receptor function were studied using electrophysiological methods and cultured rat hippocampal neurons. Fluorination at C-3 results in either subtle or pronounced effects on the pharmacological activity of the compounds. When hydrogens are replaced with fluorines at the methylene carbon of an ethyl group, as in 3-(1,1-difluoroethyl)dihydro-3-methyl-2(3H)-furanone (1), the anticonvulsant actions of the compound are not much changed from those found for the corresponding alkyl-substituted analogue. In marked contrast, fluorination at the methyl carbon of the ethyl group, as in dihydro-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 trifluoromethyl group. Results obtained with γ-butyrolactones containing either a 3-(1-trifluoromethyl)ethyl or a 3-(1-methyl-1-trifluoromethyl)ethyl substitutent indicate that the interactions of the trifluoromethyl group with the picrotoxin binding site are subject to both stereochemical and steric constraints. Sulfur for oxygen heteroatom substitution, as in the corresponding γ-thiobutyrolactones, affects the type (competitive, noncompetitive, etc.) of binding interactions that these compounds have with the picrotoxin site in a complex manner. Fluorination of alkyl groups at the C-4 and C-5 positions of γ-butyrolactones having convulsant activity increases convulsant potency.

Original languageEnglish
Pages (from-to)43-55
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume6
Issue number1
DOIs
StatePublished - Jan 1 1998

Keywords

  • Fluoroalkyl
  • GABA(A) receptor
  • Picrotoxin
  • γ-Butyrolactones
  • γ-Thiobutyrolactones

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