Trends in Pharmacological Sciences
PrinciplesAnalysis of agonist action using the operational model
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Cited by (28)
Analysis of Biased Agonism
2018, Progress in Molecular Biology and Translational ScienceCitation Excerpt :But how do we account for the relationship between receptor activation and the measured response? There is a simple solution to this problem known as the transducer function of the operational model and I cannot think of a better explanation of its theoretical basis than that given by Leff, one of its inventors45: “The operational model was derived using the simple piece of logic that if one knows about the beginning and end of a process, one can deduce what happens in the middle.”
Multiple active receptor conformation, agonist efficacy and maximum effect of the system: The conformation-based operational model of agonism
2013, Drug Discovery TodayCitation Excerpt :Although the latter assumption has been criticised [3] because it implies the use of an explicit relationship for an unknown post-receptor scenario, it has, in contrast to more-conservative null methods, the advantage of enabling a direct fitting to experimental E/[A] data [4]. It is worth emphasising that, notwithstanding the conceptual concerns derived for explicitly including a transducer function, the successful analysis by the operational model of E/[A] curves arising from many different receptor systems indicates that the model is of general applicability within the theoretical framework in which it was defined [5]. The operational model (Box 1; Equation IV) includes four parameters: KA, the agonist–receptor dissociation constant; τ, the operational efficacy of the agonist in the system; n, a parameter allowing for curves with slopes flatter or steeper than a rectangular hyperbola; and Em, the maximum effect of the system.
What ligand-gated ion channels can tell us about the allosteric regulation of G protein-coupled receptors
2013, Progress in Molecular Biology and Translational ScienceCitation Excerpt :Scientists usually measure drug effects at a point downstream in the signaling pathway of a GPCR because it is difficult to measure receptor activation directly. Nonetheless, techniques have been developed to infer Kobs and a relative value of ɛ using a null method (i.e., a type of response-clamp analysis)6 or the operational model (i.e., reverse engineering).8,9 Both methods yield the same population parameters.
Analysis of receptor inactivation experiments with the operational model of agonism yields correlated estimates of agonist affinity and efficacy
1999, Journal of Pharmacological and Toxicological MethodsAssessing the distribution of parameters in models of ligand-receptor interaction: To log or not to log
1998, Trends in Pharmacological SciencesCalculation of agonist efficacy, apparent affinity, and receptor population changes after administration of insurmountable antagonists: Comparison of different analytical approaches
1996, Journal of Pharmacological and Toxicological Methods