Linked Life Data

9502104

Source:http://linkedlifedata.com/resource/pubmed/id/9502104

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1998-5-1
pubmed:abstractText
Dihydro-2(3H)-furanones (gamma-butyrolactones) and dihydro-2(3H)-thiophenones (gamma-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 GABAA receptors were investigated. The effects of the compounds on GABAA 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 GABAA receptors caused by an interaction that involves the trifluoromethyl group. Results obtained with gamma-butyrolactones containing either a 3-(1-trifluoromethyl)ethyl or a 3-(1-methyl-1-trifluoromethyl)ethyl substituent 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 gamma-thiobutyrolactones, affects the type (competitive, non-competitive, 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 gamma-butyrolactones having convulsant activity increases convulsant potency.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0968-0896
pubmed:author
pubmed:issnType
Print
pubmed:volume
6
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
43-55
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:9502104-4-Butyrolactone, pubmed-meshheading:9502104-Animals, pubmed-meshheading:9502104-Anticonvulsants, pubmed-meshheading:9502104-Bicyclo Compounds, Heterocyclic, pubmed-meshheading:9502104-Binding, Competitive, pubmed-meshheading:9502104-Cells, Cultured, pubmed-meshheading:9502104-Convulsants, pubmed-meshheading:9502104-Electrophysiology, pubmed-meshheading:9502104-Female, pubmed-meshheading:9502104-Fluorine Compounds, pubmed-meshheading:9502104-Furans, pubmed-meshheading:9502104-GABA Modulators, pubmed-meshheading:9502104-Hippocampus, pubmed-meshheading:9502104-Mice, pubmed-meshheading:9502104-Neurons, pubmed-meshheading:9502104-Picrotoxin, pubmed-meshheading:9502104-Rats, pubmed-meshheading:9502104-Receptors, GABA-A, pubmed-meshheading:9502104-Structure-Activity Relationship
pubmed:year
1998
pubmed:articleTitle
Structure-activity studies of fluoroalkyl-substituted gamma-butyrolactone and gamma-thiobutyrolactone modulators of GABA(A) receptor function.
pubmed:affiliation
Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA 19140, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't