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
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
    • 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 molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

Evaluation of operational models of agonism and allosterism at receptors with multiple orthosteric binding sites

Karen J. Gregory, Jesus Giraldo, Jiayin Daio, Arthur Christopoulos and Katie Leach
Molecular Pharmacology November 18, 2019, mol.119.118091; DOI: https://doi.org/10.1124/mol.119.118091
Karen J. Gregory
1 Monash University;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jesus Giraldo
2 Universitat Autonoma de Barcelona
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jiayin Daio
1 Monash University;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Arthur Christopoulos
1 Monash University;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Katie Leach
1 Monash University;
  • 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 + SI
  • PDF
Loading

Abstract

Current operational models of agonism and allosterism quantify ligand actions at receptors where agonist concentration-response relationships are non-hyperbolic by introduction of a transducer slope that relates receptor occupancy to response. However, for some receptors, non-hyperbolic concentration-response relationships arise from multiple endogenous agonist molecules binding to a receptor in a cooperative manner. Thus, we developed operational models of agonism in systems with cooperative agonist binding, and evaluated the models by simulating data describing agonist effects. The models were validated by analyzing experimental data demonstrating the effects of agonists and allosteric modulators at receptors where agonist binding follows hyperbolic (M4 muscarinic acetylcholine receptors) or non-hyperbolic relationships (metabotropic glutamate receptor 5 and calcium-sensing receptor). For hyperbolic agonist-concentration response relationships, no difference in estimates of ligand affinity, efficacy or cooperativity were observed when the slope was assigned to either a transducer slope or to an agonist binding slope. In contrast, for receptors with non-hyperbolic agonist concentration-response relationships, estimates of ligand affinity, efficacy or cooperativity varied depending on the assignment of the slope. The extent of this variation depended upon the magnitude of the slope value, agonist efficacy, and, for allosteric modulators, on the magnitude of cooperativity. The modified operational models described herein are well suited to analyzing agonist and modulator interactions at receptors that bind multiple orthosteric agonists in a cooperative manner. Accounting for cooperative agonist binding is essential to accurately quantify agonist and drug actions.

SIGNIFICANCE STATEMENT Some orthosteric agonists bind to multiple sites on a receptor, but current analytical methods to characterize such interactions are limited. Herein, we develop and validate operational models of agonism and allosterism for receptors with multiple orthosteric binding sites, and demonstrate that such models are essential to accurately quantify agonist and drug actions. These findings have important implications for the discovery and development of drugs targeting receptors such as the calcium-sensing receptor, which binds at least five calcium ions.

  • Allosterism
  • Calcium
  • G protein-coupled receptors (GPCRs)
  • The American Society for Pharmacology and Experimental Therapeutics
Next
Back to top

In this issue

Molecular Pharmacology: 99 (2)
Molecular Pharmacology
Vol. 99, Issue 2
1 Feb 2021
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • 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.
Evaluation of operational models of agonism and allosterism at receptors with multiple orthosteric binding sites
(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

Evaluation of operational models of agonism and allosterism at receptors with multiple orthosteric binding sites

Karen J. Gregory, Jesus Giraldo, Jiayin Daio, Arthur Christopoulos and Katie Leach
Molecular Pharmacology November 18, 2019, mol.119.118091; DOI: https://doi.org/10.1124/mol.119.118091

Citation Manager Formats

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

Evaluation of operational models of agonism and allosterism at receptors with multiple orthosteric binding sites

Karen J. Gregory, Jesus Giraldo, Jiayin Daio, Arthur Christopoulos and Katie Leach
Molecular Pharmacology November 18, 2019, mol.119.118091; DOI: https://doi.org/10.1124/mol.119.118091
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
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • P2X7 Positive Modulator Structure-Activity Relationship
  • Predicting Drug Interactions with ENT1 and ENT2
  • GABAAR Molecular Identity in Oligodendrocytes
Show more Article

Similar Articles

  • 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 © 2021 by the American Society for Pharmacology and Experimental Therapeutics