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)-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.
Canney
D J
DJ
Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA 19140, USA.
Lu
H F
HF
McKeon
A C
AC
Yoon
K W
KW
Xu
K
K
Holland
K D
KD
Rothman
S M
SM
Ferrendelli
J A
JA
Covey
D F
DF
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001667:Binding, Competitive; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002478:Cells, Cultured; D003292:Convulsants / Q000494:pharmacology*; D004594:Electrophysiology; D005260:Female; D017611:Fluorine Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010852:Picrotoxin / Q000737:chemistry; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship
D015107:4-Butyrolactone; D000927:Anticonvulsants; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D017611:Fluorine Compounds; D005663:Furans; D018757:GABA Modulators; D010852:Picrotoxin; D011963:Receptors, GABA-A; C111614:3-(1,1-difluoroethyl)dihydro-3-methyl-2(3H)-furanone; C111615:dihydro-3-methyl-3-(2,2,2-trifluoroethyl)-2(3H)-furanone; C037476:tert-butylbicyclophosphorothionate; C083047:gamma-thiobutyrolactone