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

A Novel Selective Allosteric Modulator Potentiates the Activity of Native Metabotropic Glutamate Receptor Subtype 5 in Rat Forebrain

Julie A. O'Brien, Wei Lemaire, Marion Wittmann, Marlene A. Jacobson, Sookhee N. Ha, David D. Wisnoski, Craig W. Lindsley, Hervé J. Schaffhauser, Blake Rowe, Cyrille Sur, Mark E. Duggan, Douglas J. Pettibone, P. Jeffrey Conn and David L. Williams Jr.
Journal of Pharmacology and Experimental Therapeutics May 2004, 309 (2) 568-577; DOI: https://doi.org/10.1124/jpet.103.061747
Julie A. O'Brien
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wei Lemaire
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marion Wittmann
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marlene A. Jacobson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sookhee N. Ha
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David D. Wisnoski
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Craig W. Lindsley
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hervé J. Schaffhauser
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Blake Rowe
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cyrille Sur
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark E. Duggan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Douglas J. Pettibone
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
P. Jeffrey Conn
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David L. Williams Jr.
  • 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

We found that N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA), is a potent and selective positive allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). CPPHA alone had no agonist activity and acted as a selective positive allosteric modulator of human and rat mGluR5. CPPHA potentiated threshold responses to glutamate in fluorometric Ca2+ assays 7- to 8-fold with EC50 values in the 400 to 800 nM range, and at 10 μM shifted mGluR5 agonist concentration-response curves to glutamate, quisqualate, and (R,S)-3,5-dihydroxyphenylglycine (DHPG) 4- to 7-fold to the left. The only effect of CPPHA on other mGluRs was weak inhibition of mGluR4 and 8. Neither CPPHA nor the previously described 3,3′-difluorobenzaldazine (DFB) affected [3H]quisqualate binding to mGluR5, but although DFB partially competed for [3H]3-methoxy-5-(2-pyridinylethynyl)pyridine binding, CPPHA had no effect on the binding of this 2-methyl-6-(phenylethynyl)-pyridine analog to mGluR5. Although the binding sites for the two classes of allosteric modulators seem to be different, these different allosteric sites can modulate functionally and mechanistically similar allosteric effects. In electrophysiological studies of brain slice preparations, it had been previously shown that activation of mGluR5 receptors by agonists increased N-methyl-d-aspartate (NMDA) receptor currents in the CA1 region of hippocampal slices. We found that CPPHA (10 μM) potentiated NMDA receptor currents in hippocampal slices induced by threshold levels of DHPG, whereas having no effect on these currents by itself. Similarly, 10 μM CPPHA also potentiated mGluR5-mediated DHPG-induced depolarization of rat subthalamic nucleus neurons. These results demonstrate that allosteric potentiation of mGluR5 increases the effect of threshold agonist concentrations in native systems.

Footnotes

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

  • DOI: 10.1124/jpet.103.061747.

  • ABBREVIATIONS: mGluR, metabotropic glutamate receptor; GPCR, G protein-coupled receptor; MPEP, 2-methyl-6-(phenylethynyl)-pyridine; DFB, 3,3′-difluorobenzaldazine; CPPHA, N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide; LC/MS, liquid chromatography/mass spectrometry; TFA, trifluoroacetic acid; CHO, Chinese hamster ovary; methoxy-PEPy, 3-methoxy-5-(2-pyridinylethynyl)pyridine; STN, subthalamic nucleus; ACSF, artificial cerebrospinal fluid; NMDA, N-methyl-d-aspartate; DHPG, (R,S)-3,5-dihydroxyphenylglycine; FLIPR, fluorometric imaging plate reader; 4C3HPG, 4-carboxy,3-hydroxyphenylglcyine; PPI, prepulse inhibition; QX314, N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide; SIB-1893, 2-methyl-6-(phenylethynyl) pyridine hydrochloride; PHCCC, N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxyamide; RO 67-7476, 2-(4-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]pyrrolidine.

    • Received October 17, 2003.
    • Accepted January 26, 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.
A Novel Selective Allosteric Modulator Potentiates the Activity of Native Metabotropic Glutamate Receptor Subtype 5 in Rat Forebrain
(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

A Novel Selective Allosteric Modulator Potentiates the Activity of Native Metabotropic Glutamate Receptor Subtype 5 in Rat Forebrain

Julie A. O'Brien, Wei Lemaire, Marion Wittmann, Marlene A. Jacobson, Sookhee N. Ha, David D. Wisnoski, Craig W. Lindsley, Hervé J. Schaffhauser, Blake Rowe, Cyrille Sur, Mark E. Duggan, Douglas J. Pettibone, P. Jeffrey Conn and David L. Williams
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 568-577; DOI: https://doi.org/10.1124/jpet.103.061747

Citation Manager Formats

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

A Novel Selective Allosteric Modulator Potentiates the Activity of Native Metabotropic Glutamate Receptor Subtype 5 in Rat Forebrain

Julie A. O'Brien, Wei Lemaire, Marion Wittmann, Marlene A. Jacobson, Sookhee N. Ha, David D. Wisnoski, Craig W. Lindsley, Hervé J. Schaffhauser, Blake Rowe, Cyrille Sur, Mark E. Duggan, Douglas J. Pettibone, P. Jeffrey Conn and David L. Williams
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 568-577; DOI: https://doi.org/10.1124/jpet.103.061747
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

  • 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