Structure-activity studies of fluoroalkyl-substituted gamma-butyrolactone and gamma-thiobutyrolactone modulators of GABA(A) receptor function
| Autor: | Katherine D. Holland, Kun Xu, Kong Woo Yoon, Steven M. Rothman, Douglas F. Covey, Ann C. McKeon, Daniel J. Canney, James A. Ferrendelli, Hwang Fun Lu |
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| Rok vydání: | 1998 |
| Předmět: |
Steric effects
Stereochemistry Clinical Biochemistry Fluorine Compounds Pharmaceutical Science Convulsants Biochemistry Binding Competitive Hippocampus chemistry.chemical_compound Mice Structure-Activity Relationship 4-Butyrolactone Drug Discovery Animals Picrotoxin Ethyl group Binding site Furans GABA Modulators Molecular Biology Cells Cultured Neurons Trifluoromethyl GABAA receptor Organic Chemistry Biological activity Bridged Bicyclo Compounds Heterocyclic Receptors GABA-A Rats Electrophysiology chemistry Convulsant Molecular Medicine Anticonvulsants Female |
| Zdroj: | Bioorganicmedicinal chemistry. 6(1) |
| ISSN: | 0968-0896 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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