Abstract
AbstractThe fitting of complex receptor-response data where fractional response and occupancy do not match is challenging. They encompass important cases including (a) the presence of “receptor reserve” and/or partial agonism, (b) multiple responses assessed at different vantage points along a pathway, (c) responses that are different along diverging downstream pathways (biased agonism), and (d) constitutive activity. For these, simple models such as the well-known Clark or Hill equations cannot be used. Those that can, such as the operational (Black&Leff) model, do not provide a unified approach, have multiple nonintuitive parameters that are challenging to fit in well-defined manner, have difficulties incorporating binding data, and cannot be reduced or connected to simpler forms. We have recently introduced a quantitative receptor model (SABRE) that includes parameters for Signal Amplification (γ), Binding affinity (Kd), Receptor activation Efficacy (ε), and constitutive activity (εR0). It provides a single equation to fit complex cases within a full two-state framework with the possibility of incorporating receptor occupancy data (i.e., experimental Kds). Simpler cases can be fit by using consecutively reduced forms obtained by constraining parameters to specific values, e.g., εR0 = 0: no constitutive activity, γ = 1: no amplification (Emax-type fitting), and ε = 1: no partial agonism (Clark equation). Here, a Hill-type extension is introduced (n ≠ 1), and simulated and experimental receptor-response data from simple to increasingly complex cases are fitted within the unified framework of SABRE with differently constrained parameters.
Funder
National Institutes of Health, National Institute of Allergy and Infectious Diseases
Publisher
Springer Science and Business Media LLC
Reference58 articles.
1. Rang, H. P. The receptor concept: pharmacology’s big idea. Br. J. Pharmacol.147, S9–S16 (2006).
2. Maehle, A.-H., Prüll, C.-R. & Halliwell, R. F. The emergence of the drug receptor theory. Nat. Rev. Drug Discov.1, 637–641 (2002).
3. Jenkinson, D. H. Classical approaches to the study of drug-receptor interactions. In Textbook of Receptor Pharmacology (eds Foreman, J. C. et al.) 3–78 (CRC Press, Boca Raton, 2010).
4. Ehlert, F. J. Affinity and Efficacy: The Components of Drug–Receptor Interactions (World Scientific, Singapore, 2015).
5. Kenakin, T. P. A Pharmacology Primer: Techniques for More Effective and Strategic Drug Discovery 5th edn. (Academic Press, London, 2018).
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