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Proper determination of agonist efficacy is essential in the assessment of agonist selectivity and signalling bias. Agonist efficacy is a relative term that is dependent on the system in which it is measured, especially being dependent on receptor expression level. The operational model (OM) of functional receptor agonism is a useful means for the determination of agonist functional efficacy using the maximal response to agonist and ratio of agonist functional potency to its equilibrium dissociation constant (K A ) at the active state of the receptor. However, the functional efficacy parameter τ is inter-dependent on two other parameters of OM; agonist’s K A  and the highest response that could be evoked in the system by any stimulus (E MAX ). Thus, fitting of OM to functional response data is a tricky process. In this work we analyse pitfalls of fitting OM to experimental data and propose a rigorous fitting procedure where K A  and E MAX  are derived from half-efficient concentration of agonist and apparent maximal responses obtained from a series of functional response curves. Subsequently, OM with fixed K A  and E MAX  is fitted to functional response data to obtain τ. The procedure was verified at M 2  and M 4  muscarinic receptors fused with the G 15  G-protein α-subunit. The procedure, however, is applicable to any receptor-effector system.

Applications and limitations of fitting of the operational model to determine relative efficacies of agonists