Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • 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
  • Submit
  • 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
  • Log out
  • My Cart

Search

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

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • 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
  • Submit
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

Mutational Analysis and Molecular Modeling of the Binding Pocket of the Metabotropic Glutamate 5 Receptor Negative Modulator 2-Methyl-6-(phenylethynyl)-pyridine

Pari Malherbe, Nicole Kratochwil, Marie-Théeése Zenner, Jenny Piussi, Catherine Diener, Claudia Kratzeisen, Christophe Fischer and Richard H. P. Porter
Molecular Pharmacology October 2003, 64 (4) 823-832; DOI: https://doi.org/10.1124/mol.64.4.823
Pari Malherbe
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nicole Kratochwil
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marie-Théeése Zenner
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jenny Piussi
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Catherine Diener
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Claudia Kratzeisen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christophe Fischer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard H. P. Porter
  • 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

Metabotropic glutamate (mGlu) 5 is a G-protein-coupled metabotropic glutamate receptor that plays an important role as a modulator of synaptic plasticity, ion channel activity, and excitotoxicity. 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) is a highly potent, noncompetitive, selective, and systemically active antagonist of mGlu5 receptors. It binds to a novel allosteric site that resides within the seven-transmembrane domain of mGlu5 receptors. Using site-directed mutagenesis, [3H]MPEP binding, a functional Ca2+ mobilization assay, and rhodopsin-based homology modeling, we identified eight residues (Pro-6543.36, Tyr-6583.40, Leu-7435.47, Thr-7806.44, Trp-7846.48, Phe-7876.51, Tyr-7916.55, and Ala-8097.47) that are crucial for MPEP-binding to rat mGlu5 receptors. Four mutations, Y6583.40V, W7846.48A, F7876.51A, and A8097.47V, caused complete loss of [3H]MPEP binding and also blocked the MPEP-mediated inhibition of quisqualate-induced intracellular Ca2+ mobilization. To visualize these experimental findings, we have constructed a homology model based on the X-ray crystal of bovine rhodopsin and have suggested a possible binding mode of MPEP. We propose that MPEP via its interactions with a network of the aromatic residues including Phe-6583.40 in transmembrane (TM) 3 helix and Trp-7986.48, Phe-7876.51, and Tyr-7916.55 in TM6 helix prevents the movement of TM6 helix relative to TM3 helix, a step that is required for receptor activation, and consequently stabilizes the inactive conformation of mGlu5 receptor. In the TM6 region, we observed a striking similarity between the critical residues involved in MPEP-binding site with those of previously identified as 1-ethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydropyrimidine-5-carbonitrile-binding pocket of mGlu1, pointing to a common mechanism of inhibition shared by both antagonists.

  • Received May 1, 2003.
  • Accepted July 1, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm 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

Molecular Pharmacology: 64 (4)
Molecular Pharmacology
Vol. 64, Issue 4
1 Oct 2003
  • 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 Molecular Pharmacology 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.
Mutational Analysis and Molecular Modeling of the Binding Pocket of the Metabotropic Glutamate 5 Receptor Negative Modulator 2-Methyl-6-(phenylethynyl)-pyridine
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Mutational Analysis and Molecular Modeling of the Binding Pocket of the Metabotropic Glutamate 5 Receptor Negative Modulator 2-Methyl-6-(phenylethynyl)-pyridine

Pari Malherbe, Nicole Kratochwil, Marie-Théeése Zenner, Jenny Piussi, Catherine Diener, Claudia Kratzeisen, Christophe Fischer and Richard H. P. Porter
Molecular Pharmacology October 1, 2003, 64 (4) 823-832; DOI: https://doi.org/10.1124/mol.64.4.823

Citation Manager Formats

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

Share
Research ArticleArticle

Mutational Analysis and Molecular Modeling of the Binding Pocket of the Metabotropic Glutamate 5 Receptor Negative Modulator 2-Methyl-6-(phenylethynyl)-pyridine

Pari Malherbe, Nicole Kratochwil, Marie-Théeése Zenner, Jenny Piussi, Catherine Diener, Claudia Kratzeisen, Christophe Fischer and Richard H. P. Porter
Molecular Pharmacology October 1, 2003, 64 (4) 823-832; DOI: https://doi.org/10.1124/mol.64.4.823
del.icio.us logo Digg logo Reddit logo Twitter 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

  • Fatty acid amide hydrolase in cisplatin nephrotoxicity
  • eCB Signaling System in hiPSC-Derived Neuronal Cultures
  • Benzbromarone relaxes airway smooth muscle via BK activation
Show more Article

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 Molecular Pharmacology
  • 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
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics