An intact model for quantifying functional selectivity

Scientific Reports
Xiao ZhuStephen B Duffull

Abstract

A ligand that acts on a target receptor to activate particular multiple signalling pathways with activity that is distinct from other ligands is termed ligand bias. Quantification of ligand bias is based on applying the operational model to each pathway separately and subsequent calculation of the ligand bias metric (ΔΔlogR). This approach implies independence among different pathways and causes propagation of error in the calculation. Here, we propose a semi-mechanism-based model which allows for receptor selectivity across all the pathways simultaneously (termed the 'intact operational model'). The power of the intact model for detecting ligand bias was evaluated via stochastic simulation estimation studies. It was also applied to two examples: (1) opposing effects of Gi/Gs signalling of α2-adrenergic receptors and (2) simultaneous measurement of arachidonic acid release and inositol phosphate accumulation following 5-HT2C receptor activation. The intact operational model demonstrated greater power to detect ligand bias in the simulation. In the applications, it provided better precision of estimation and identified biased ligands that were missed by analysis of traditional methods. Issues identified in both examples might le...Continue Reading

References

Dec 22, 1983·Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character·J W Black, P Leff
Jun 29, 2006·The Journal of Pharmacology and Experimental Therapeutics·Jonathan D UrbanRichard B Mailman
Jul 11, 2007·Journal of Pharmacokinetics and Pharmacodynamics·Yaning Wang
May 26, 2011·Molecular Pharmacology·Sudarshan RajagopalRobert J Lefkowitz
Aug 4, 2012·ACS Chemical Neuroscience·Terry KenakinSteven Novick
Feb 16, 2013·Nature Reviews. Drug Discovery·Terry Kenakin, Arthur Christopoulos
May 18, 2013·Nature Reviews. Drug Discovery·Terry Kenakin, Arthur Christopoulos
May 18, 2013·Nature Reviews. Drug Discovery·Sudarshan Rajagopal
Jul 10, 2013·CPT: Pharmacometrics & Systems Pharmacology·R J KeizerA Hooker
Dec 3, 2014·Trends in Pharmacological Sciences·H Ongun OnaranTommaso Costa
Feb 26, 2016·Nature Communications·Carmen Klein HerenbrinkJ Robert Lane
Feb 20, 2018·British Journal of Pharmacology·Xiao ZhuStephen B Duffull

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Citations

Apr 16, 2020·British Journal of Pharmacology·Xiao ZhuStephen B Duffull

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Software Mentioned

Xpose
GraphPad Prism
Perl
Pirana
Prism
Phoenix NLME
Monolix
NONMEM

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