Conceptual and experimental issues in biased agonism.

In this review, we discuss the theoretical and experimental foundations for assessing agonism in the context of signalling bias in GPCRs. We show that the formulation of efficacy in classical receptor theory and the definition of ligand-induced allosteric effect in chemical thermodynamics are coincident measures of agonism, only if we recognize that the classical model cannot be considered as a mechanistic description of the physicochemical events underlying ligand-receptor signalling. It represents instead a mathematical tool, fortuitously capable of extracting efficacy information from concentration-dependent functional data, where both ligand-dependent and ligand-independent information are present. We also assert that dissecting efficacy from affinity, as originally advocated in classical theory, is imperative for understanding the molecular property underlying agonism, and the biased agonism that leads to preferential formation of diverse GPCR-transducer complexes. Finally, we argue that beyond the assumed translational value of functional selectivity (i.e. signalling bias), the identification of ligands with true bias of efficacy is of fundamental importance for unravelling the conformational space that determines the complex functional chemistry of GPCRs.

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