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
  • 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
  • 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

A Novel Drug Binding Site on Voltage-Gated Sodium Channels in Rat Brain

Dieter R. Riddall, Michael J. Leach and John Garthwaite
Molecular Pharmacology January 2006, 69 (1) 278-287; DOI: https://doi.org/10.1124/mol.105.015966
Dieter R. Riddall
Wolfson Institute for Biomedical Research, University College London, London United Kingdom (D.R.R., J.G.); and School of Science and School of Pharmacy, University of Greenwich at Medway, Chatham Maritime, United Kingdom (M.J.L.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael J. Leach
Wolfson Institute for Biomedical Research, University College London, London United Kingdom (D.R.R., J.G.); and School of Science and School of Pharmacy, University of Greenwich at Medway, Chatham Maritime, United Kingdom (M.J.L.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John Garthwaite
Wolfson Institute for Biomedical Research, University College London, London United Kingdom (D.R.R., J.G.); and School of Science and School of Pharmacy, University of Greenwich at Medway, Chatham Maritime, United Kingdom (M.J.L.)
  • 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

The effectiveness of several antiepileptic, analgesic, and neuroprotective drugs is attributable to state-dependent inhibition of voltage-gated sodium channels. To help characterize their site and mode of action on sodium channels, a member of the lamotrigine family, R-(-)-2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)-pyrimidine (BW202W92), was radiolabeled and used as a binding ligand in rat forebrain synaptosomes. Although the level of specific [3H]BW202W92 binding in a standard incubation medium was relatively poor, low concentrations of tetrodotoxin (EC50 = 2-3 nM) greatly enhanced the binding, apparently by increasing the affinity of the binding sites. Tetrodotoxin-dependent binding was stereoselective (the less active enantiomer, S-(-)-2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)-pyrimidine (BW203W92), was up to 30-fold less potent, depending on conditions) and was extremely sensitive to inhibition by raised K+ concentration (IC50 = 5.9 mM), an effect that was ascribed to changes in membrane potential. In addition, the binding was inhibited by sodium channel neurotoxins acting on sites 3 and 4, but it was resistant to batrachotoxin (site 2) and brevetoxin (site 5). Several drugs acting on sodium channels displaced tetrodotoxin-dependent [3H]BW202W92 binding, and most of those tested showed different affinities under depolarized (100 mM K+) and polarized (1 mM K+) conditions. In a subset of compounds for which data were available, binding affinity in depolarized synaptosomes correlated well with apparent affinity for the inactivated state of sodium channels. The [3H]BW202W92 binding site is novel and is likely to represent a pharmacologically important site of action of drugs on voltage-gated sodium channels in the brain.

  • 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: 69 (1)
Molecular Pharmacology
Vol. 69, Issue 1
1 Jan 2006
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
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.
A Novel Drug Binding Site on Voltage-Gated Sodium Channels in Rat Brain
(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

A Novel Drug Binding Site on Voltage-Gated Sodium Channels in Rat Brain

Dieter R. Riddall, Michael J. Leach and John Garthwaite
Molecular Pharmacology January 1, 2006, 69 (1) 278-287; DOI: https://doi.org/10.1124/mol.105.015966

Citation Manager Formats

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

Share
Research ArticleArticle

A Novel Drug Binding Site on Voltage-Gated Sodium Channels in Rat Brain

Dieter R. Riddall, Michael J. Leach and John Garthwaite
Molecular Pharmacology January 1, 2006, 69 (1) 278-287; DOI: https://doi.org/10.1124/mol.105.015966
Reddit logo Twitter logo Facebook 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

  • Differential Drug Effects on Homo/Heteromeric hERG Channels
  • ACKR3 Senses CXCR4 Activation Through GRK Phosphorylation
  • Analgesic Effects and Mechanisms of Licochalcones
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