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

Allosteric Modulation of the Cannabinoid CB1 Receptor

Martin R. Price, Gemma L. Baillie, Adèle Thomas, Lesley A. Stevenson, Morag Easson, Richard Goodwin, Adèle McLean, Lorraine McIntosh, Gillian Goodwin, Glenn Walker, Paul Westwood, Julia Marrs, Fiona Thomson, Phillip Cowley, Arthur Christopoulos, Roger G. Pertwee and Ruth A. Ross
Molecular Pharmacology November 2005, 68 (5) 1484-1495; DOI: https://doi.org/10.1124/mol.105.016162
Martin R. Price
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gemma L. Baillie
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Adèle Thomas
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lesley A. Stevenson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Morag Easson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard Goodwin
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Adèle McLean
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lorraine McIntosh
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gillian Goodwin
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Glenn Walker
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul Westwood
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Julia Marrs
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Fiona Thomson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Phillip Cowley
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Arthur Christopoulos
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Roger G. Pertwee
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ruth A. Ross
  • 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 investigated the pharmacology of three novel compounds, Org 27569 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)-ethyl]-amide), Org 27759 (3-ethyl-5-fluoro-1H-indole-2-carboxylic acid [2-94-dimethylamino-phenyl)-ethyl]-amide), and Org 29647 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid (1-benzyl-pyrrolidin-3-yl)-amide, 2-enedioic acid salt), at the cannabinoid CB1 receptor. In equilibrium binding assays, the Org compounds significantly increased the binding of the CB1 receptor agonist [3H]CP 55,940 [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol], indicative of a positively cooperative allosteric effect. The same compounds caused a significant, but incomplete, decrease in the specific binding of the CB1 receptor inverse agonist [3H]SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride], indicative of a limited negative binding cooperativity. Analysis of the data according to an allosteric ternary complex model revealed that the estimated affinity of each Org compound was not significantly different when the radioligand was [3H]CP 55,940 or [3H]SR 141716A. However, the estimated cooperatively factor for the interaction between modulator and radioligand was greater than 1 when determined against [3H]CP 55,940 and less than 1 when determined against [3H]SR 141716A. [3H]CP 55,940 dissociation kinetic studies also validated the allosteric nature of the Org compounds, because they all significantly decreased radioligand dissociation. These data suggest that the Org compounds bind allosterically to the CB1 receptor and elicit a conformational change that increases agonist affinity for the orthosteric binding site. In contrast to the binding assays, however, the Org compounds behaved as insurmountable antagonists of receptor function; in the reporter gene assay, the guanosine 5′-O-(3-[35S]thio)triphosphate binding assay and the mouse vas deferens assay they elicited a significant reduction in the Emax value for CB1 receptor agonists. The data presented clearly demonstrate, for the first time, that the cannabinoid CB1 receptor contains an allosteric binding site that can be recognized by synthetic small molecule ligands.

  • Received June 28, 2005.
  • Accepted August 18, 2005.
  • 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: 68 (5)
Molecular Pharmacology
Vol. 68, Issue 5
1 Nov 2005
  • 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.
Allosteric Modulation of the Cannabinoid CB1 Receptor
(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

Allosteric Modulation of the Cannabinoid CB1 Receptor

Martin R. Price, Gemma L. Baillie, Adèle Thomas, Lesley A. Stevenson, Morag Easson, Richard Goodwin, Adèle McLean, Lorraine McIntosh, Gillian Goodwin, Glenn Walker, Paul Westwood, Julia Marrs, Fiona Thomson, Phillip Cowley, Arthur Christopoulos, Roger G. Pertwee and Ruth A. Ross
Molecular Pharmacology November 1, 2005, 68 (5) 1484-1495; DOI: https://doi.org/10.1124/mol.105.016162

Citation Manager Formats

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

Share
Research ArticleArticle

Allosteric Modulation of the Cannabinoid CB1 Receptor

Martin R. Price, Gemma L. Baillie, Adèle Thomas, Lesley A. Stevenson, Morag Easson, Richard Goodwin, Adèle McLean, Lorraine McIntosh, Gillian Goodwin, Glenn Walker, Paul Westwood, Julia Marrs, Fiona Thomson, Phillip Cowley, Arthur Christopoulos, Roger G. Pertwee and Ruth A. Ross
Molecular Pharmacology November 1, 2005, 68 (5) 1484-1495; DOI: https://doi.org/10.1124/mol.105.016162
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
    • Appendix
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • The binding site for KCI807 in the androgen receptor
  • Fatty acid amide hydrolase in cisplatin nephrotoxicity
  • eCB Signaling System in hiPSC-Derived Neuronal Cultures
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