JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yoon, K. W.
Right arrow Articles by Rothman, S. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yoon, K. W.
Right arrow Articles by Rothman, S. M.

Modulation of the picrotoxin receptor by fluorinated ethyl, methyl- butyrolactones

KW Yoon, DJ Canney, DF Covey and SM Rothman

Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.

A number of investigators have shown that gamma-butyrolactones bind to the picrotoxin site on the gamma-aminobutyric acid (GABA) receptor. We examined the effects of three fluorinated gamma-butyrolactone derivatives on GABA currents and synaptic currents in cultured hippocampal neurons. alpha-(2,2,2-trifluoroethyl)-alpha-methyl-gamma- butyrolactone was a partial picrotoxin agonist, meaning that like picrotoxin, it blocked GABA currents, but not completely. This action is in marked contrast to that of its parent compound, alpha-ethyl-alpha- methyl-gamma-butyrolactone, which is a mixed inverse agonist/antagonist, enhancing GABA currents at low GABA concentration (less than or equal to 1 microM) and antagonizing picrotoxin block of GABA currents at higher GABA concentrations (approximately 30 microM). The properties of two difluorinated derivatives were found to be very different from the trifluorinated compound. Both alpha-(1,1- difluoroethyl)-alpha-methyl-gamma-butyrolactone and alpha-(1,1- difluoroethyl)-alpha-methyl-gamma-thiobutyrolactone+ ++ dramatically increased the current produced by low concentrations of GABA. The former had less marked inverse agonist effects at higher GABA concentrations but behaved instead like a picrotoxin antagonist. In addition, alpha-(1,1-difluoroethyl)-alpha-methyl-gamma-butyrolactone reduced both excitatory and inhibitory synaptic currents suggesting a separate effect on presynaptic transmitter release through an unknown mechanism. These experiments support the hypothesis that gamma- butyrolactones can have a variety of effects at the picrotoxin receptor and indicate that specific properties of these compounds can be altered drastically by fluorination.

Volume 255, Issue 1, pp. 248-255, 10/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
M. W. Hill, P. A. Reddy, D. F. Covey, and S. M. Rothman
Inhibition of Voltage-Dependent Sodium Channels by the Anticonvulsant gamma -Aminobutyric Acid Type A Receptor Modulator, 3-Benzyl-3-Ethyl-2-Piperidinone
J. Pharmacol. Exp. Ther., June 1, 1998; 285(3): 1303 - 1309.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
L. S. Aspinwall, I. Bermudez, L. A. King, and K. A. Wafford
The Interactions of Hexachlorocyclohexane Isomers with Human gamma -Aminobutyric AcidA Receptors Expressed in Xenopus Oocytes
J. Pharmacol. Exp. Ther., September 1, 1997; 282(3): 1557 - 1564.
[Abstract] [Full Text]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1990 by the American Society for Pharmacology and Experimental Therapeutics.