Insights into the operational model of agonism of receptor dimers

ABSTRACT

Introduction

Accurate ranking of efficacies and potencies of agonists is essential in the discovery of new selective agonists. For the purpose of system-independent ranking of agonists, the operational model of agonism (OMA) has become a standard. Many receptors function as oligomers which makes functional responses more complex, requiring an extension of the original OMA.

Areas covered

Explicit equations of the operational model of agonism of receptor dimers (OMARD) were derived. The OMARD can be applied to any receptor possessing two orthosteric sites. The behavior of OMARD was analyzed to demonstrate its complexity and relation to experimental data. Properties of OMARD and OMA equations were compared to demonstrate their pros and cons.

Expert opinion

Extension of OMA by slope factors gives simple equations of functional response that are easy to fit experimental data but results may be inaccurate because of exponentiation of operational efficacy. Also, such equations cannot accommodate bell-shaped curves. Explicit equations of OMARD give accurate results but are complex and tedious to fit experimental data. All operational models use inter-dependent parameters that are a hurdle in the fitting. A good understanding of OMARD behavior helps to overcome such obstacles.

KEYWORDS:

• Operational model of agonism
• operational efficacy
• allosteric modulation
• receptor dimers
• GPCRs
• receptor channels

Article highlights

• The exact ranking of efficacies and potencies of agonists is indispensable in the discovery of new selective agonists.

• The operational model of agonism (OMA) is the current standard.

• Many receptors function as oligomers, requiring an extension of the classical OMA.

• Extension of OMA by slope factors gives simple equations of functional response that are easy to fit experimental data but results may be inaccurate.

• Extension of OMA by cooperativity factors gives accurate but complex equations of functional response.

• Extension of OMA by cooperativity factors should be preferred.

Acknowledgments

We would like to thank Prof Esam E. El-Fakahany, University of Minnesota College of Pharmacy, and Dr Vladimír Doležal, Institute of Physiology CAS Prague, for critical reading of the manuscript.

Declaration of interests

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17460441.2023.2147502

Additional information

Funding

This research was funded by the Czech Science Foundation grant [19-06106Y] and by the Czech Academy of Sciences institutional support [RVO:67985823].