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 ArticleCELLULAR AND MOLECULAR

Compounds Exhibiting Selective Efficacy for Different β Subunits of Human Recombinant γ-Aminobutyric AcidA Receptors

Alison J. Smith, Beth Oxley, Sallie Malpas, Gopalan V. Pillai and Peter B. Simpson
Journal of Pharmacology and Experimental Therapeutics November 2004, 311 (2) 601-609; DOI: https://doi.org/10.1124/jpet.104.070342
Alison J. Smith
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Beth Oxley
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sallie Malpas
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gopalan V. Pillai
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Peter B. Simpson
  • 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

Inhibitory GABAA receptor modulators are widely used therapeutic agents for a variety of central nervous system disorders. Ltk– cells stably expressing human recombinant GABAA subunits (α1β1–3γ2s) were seeded into 96-well plates, loaded with chlorocoumarin-2-dimyristoyl phosphatidylethanolamine and bis(1,3-diethyl-2-thiobarbiturate)trimethineoxonol, and rapid fluorescence resonance energy transfer technique (FRET) measurements were made of GABA-evoked depolarizations in low-Cl– buffer using a voltage/ion probe reader. The influence of different βsubunits on the ability of agents to modulate and directly activate the ion channel was examined. GABA evoked concentration-dependent decreases in FRET, increasing fluorescence emission ratio (460/580 nm) at α1β1γ2, α1β2γ2, and α1β3γ2 receptors with similar maximal amplitude (P > 0.05, n = 17) and EC50 values of 2.4 ± 0.2, 2.5 ± 0.2, and 1.3 ± 0.1 μM, respectively. Piperidine-4-sulfonic acid and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol were less potent, with EC50 values of 8.7 ± 0.9, 9.2 ± 0.5, and 11.7 ± 1.2, and 43.7 ± 6.4, 24.8 ± 1.6, and 26.1 ± 2.4 μM, respectively. Potency and maximal efficacy of propofol, methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate, pentobarbital, and steroids, 5α-pregnan-3α-ol-20-one and 5β-pregnan-3α-ol-20-one, were unaffected by the β isoform present in the receptor complex. However, several compounds displayed β2/3 subunit selectivity, notably loreclezole, R(–)-etomidate, and a group of anti-inflammatory agents including mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic acid, niflumic acid, and diflunisal. The anti-inflammatories exhibited varying levels of efficacy at β2/3 subunits, with micromolar potency, while having antagonist or weak inverse agonist profiles at α1β1γ2. Diflunisal was the most efficacious compound, eliciting greater potentiation than loreclezole (90 ± 14% and 109 ± 14% at β3 and β2, respectively, compared with 62 ± 6% and 56 ± 3%), whereas niflumic acid exhibited the lowest efficacy. An additional agent, olsalazine, weakly potentiated responses at all three receptors without any selectivity. This study identifies and characterizes a variety of allosteric modulators for which βsubunits are an important determinant of efficacy and potency.

Footnotes

  • doi:10.1124/jpet.104.070342.

  • ABBREVIATIONS: FRET, fluorescence resonance energy transfer; DMEM, Dulbecco's modified Eagle's medium; CC2-DMPE, chlorocoumarin-2-dimyristoyl phosphatidylethanolamine; DiSBAC2(3), bis(1,3-diethyl-2-thiobarbiturate)trimethineoxonol; THIP, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; P4S, piperidine-4-sulfonic acid.

    • Received April 20, 2004.
    • Accepted June 10, 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: 311 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 311, Issue 2
1 Nov 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.
Compounds Exhibiting Selective Efficacy for Different β Subunits of Human Recombinant γ-Aminobutyric AcidA Receptors
(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 ArticleCELLULAR AND MOLECULAR

Compounds Exhibiting Selective Efficacy for Different β Subunits of Human Recombinant γ-Aminobutyric AcidA Receptors

Alison J. Smith, Beth Oxley, Sallie Malpas, Gopalan V. Pillai and Peter B. Simpson
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 601-609; DOI: https://doi.org/10.1124/jpet.104.070342

Citation Manager Formats

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

Compounds Exhibiting Selective Efficacy for Different β Subunits of Human Recombinant γ-Aminobutyric AcidA Receptors

Alison J. Smith, Beth Oxley, Sallie Malpas, Gopalan V. Pillai and Peter B. Simpson
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 601-609; DOI: https://doi.org/10.1124/jpet.104.070342
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
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • PARPi with vitamin C, decitabine or azacitidine for APL.
  • Circ-KRT6C/miR-485-3p/PDL1 axis in colorectal cancer.
  • Zebrafish Gstp1 Drug Response
Show more Cellular and Molecular

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