Insights into the operational model of agonism of receptor dimers

0566162 - FGÚ 2023 RIV GB eng J - Journal Article
Jakubík, Jan - Randáková, Alena
Insights into the operational model of agonism of receptor dimers.
Expert Opinion on Drug Discovery. Roč. 17, č. 11 (2022), s. 1181-1191. ISSN 1746-0441. E-ISSN 1746-045X
R&D Projects: GA ČR(CZ) GJ19-06106Y
Institutional support: RVO:67985823
Keywords : operational model of agonism * operational efficacy * allosteric modulation * receptor dimers * GPCRs * receptor channels
OECD category: Pharmacology and pharmacy
Impact factor: 6.3, year: 2022
Method of publishing: Limited access
https://doi.org/10.1080/17460441.2023.2147502

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.
Permanent Link: https://hdl.handle.net/11104/0337590