Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Journal of Pharmacology and Experimental Therapeutics
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Journal of Pharmacology and Experimental Therapeutics

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleNEUROPHARMACOLOGY

Enantioselectivity of α-Benzyl-α-methyl-γ-butyrolactone-Mediated Modulation of Anticonvulsant Activity and GABAA Receptor Function

Eric B. Gonzales, Cathy L. Bell-Horner, Maria Antonette M. de la Cruz, James A. Ferrendelli, Douglas F. Covey and Glenn H. Dillon
Journal of Pharmacology and Experimental Therapeutics May 2004, 309 (2) 677-683; DOI: https://doi.org/10.1124/jpet.103.063008
Eric B. Gonzales
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cathy L. Bell-Horner
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maria Antonette M. de la Cruz
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
James A. Ferrendelli
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Douglas F. Covey
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Glenn H. Dillon
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

Alkyl-substituted butyrolactones have both inhibitory and stimulatory effects on GABAA receptors. Lactones with small alkyl substitutions at the α-position positively modulate the channel, whereas β-substituted lactones tend to inhibit the GABAA receptor. These compounds mediate inhibition through the picrotoxin site of the receptor. A distinct binding site that mediates the stimulatory actions of lactones is presumed to exist, although no definitive evidence to support this claim exists. In the present study, we used in vivo and in vitro assays to evaluate the effects of the enantiomers of a novel lactone, α-benzyl-α-methyl-γ-butyrolactone (α-BnMeGBL), on the GABAA receptor. R-(-)-α-BnMeGBL was 2-fold more potent than the S-(+)-α-BnMeGBL in blocking pentylenetetrazol-induced seizures in CF-1 mice. The (+)-enantiomer inhibited binding of t-butylbicyclophosporothionate with a higher affinity than the (-)-enantiomer (IC50 of 0.68 and 1.1 mM, respectively). Whole cell patch-clamp recordings from recombinant α1β2γ2 receptors stably expressed in HEK293 cells demonstrated that both compounds stimulated GABA-activated current. The maximal stimulation was approximately 2-fold greater with (+)-α-BnMeGBL than that seen with (-)-α-BnMeGBL. Both enantiomers of α-BnMeGBL directly gated the GABAA receptor at mM concentrations, in a nonstereoselective manner. Our data demonstrate the stimulatory actions of α-BnMeGBL on GABAA receptor function display enantioselectivity and provide strong evidence for the existence of a true “lactone site” on the receptor.

Footnotes

  • This work was supported by National Institutes of Health Grant ES07904 (to G.H.D.) and NS14834 (to D.F.C.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.103.063008.

  • ABBREVIATIONS: GABAAR, type A GABA receptor; GBL, γ-butyrolactone; TBL, γ-thiobutyrolactone; TBPS, t-butylbicyclophosporothionate; α-BnMeGBL, α-benzyl-α-methyl-γ-butyrolactone; HEK, human embryonic kidney; THF, tetrahydrofuran; IR, infrared; PTZ, pentylenetetrazole.

    • Received November 14, 2003.
    • Accepted January 20, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 309 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 309, Issue 2
1 May 2004
  • Table of Contents
  • About the Cover
  • Index by author
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Journal of Pharmacology and Experimental Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Enantioselectivity of α-Benzyl-α-methyl-γ-butyrolactone-Mediated Modulation of Anticonvulsant Activity and GABAA Receptor Function
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleNEUROPHARMACOLOGY

Enantioselectivity of α-Benzyl-α-methyl-γ-butyrolactone-Mediated Modulation of Anticonvulsant Activity and GABAA Receptor Function

Eric B. Gonzales, Cathy L. Bell-Horner, Maria Antonette M. de la Cruz, James A. Ferrendelli, Douglas F. Covey and Glenn H. Dillon
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 677-683; DOI: https://doi.org/10.1124/jpet.103.063008

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleNEUROPHARMACOLOGY

Enantioselectivity of α-Benzyl-α-methyl-γ-butyrolactone-Mediated Modulation of Anticonvulsant Activity and GABAA Receptor Function

Eric B. Gonzales, Cathy L. Bell-Horner, Maria Antonette M. de la Cruz, James A. Ferrendelli, Douglas F. Covey and Glenn H. Dillon
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 677-683; DOI: https://doi.org/10.1124/jpet.103.063008
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • CVN424, a novel GPR6 inverse agonist for Parkinson's disease
  • Methylone Brain Concentrations and Pharmacodynamic Effects
  • Oxysterols and Ethanol
Show more Neuropharmacology

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About JPET
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics