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Quantifying biased agonism: understanding the links between affinity and efficacy

Nature Reviews Drug Discovery volume 12, page 483 (2013)Cite this article

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In the March issue of Nature Reviews Drug Discovery, a Perspective article by Kenakin and Christopoulos (Nature Rev. Drug Discov. 12, 205–216; 2013)1 reviewed a number of important developments in our understanding of biased agonism at G protein-coupled receptors (GPCRs; also known as seven transmembrane receptors) over the past decade. In my opinion, the authors have erred in their presentation of which approaches are most useful for measuring biased signalling at GPCRs. Such models can be broadly considered as pharmacological or allosteric models.

Allosteric models explicitly account for signalling by the formation of an agonist–receptor–transducer ternary complex6,7,8 (Fig. 1b). Unlike pharmacological models in which the agonist–receptor complex results in a different stimulus depending on the agonist, the ternary complex results in an equal stimulus for signalling regardless of which ligand is used; the efficacy of a ligand is defined by its ability to form this signalling-competent ternary complex. The formation of this ternary complex by an agonist is associated with a high-affinity binding state of the ligand for the receptor–transducer complex that is related to pharmacological efficacy6 (Fig. 1).

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Figure 1: Pharmacological and allosteric models for interpreting receptor signalling.

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Acknowledgements

The author thanks R. Lefkowitz, T. Costa and O. Onaran for invaluable discussions.

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  1. Sudarshan Rajagopal is at the Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.,

    Sudarshan Rajagopal

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  1. Sudarshan Rajagopal
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Correspondence to Sudarshan Rajagopal.

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Rajagopal, S. Quantifying biased agonism: understanding the links between affinity and efficacy. Nat Rev Drug Discov 12, 483 (2013). https://doi.org/10.1038/nrd3954-c1

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