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Cellular assays as portals to seven-transmembrane receptor-based drug discovery

Nature Reviews Drug Discovery volume 8, pages 617–626 (2009)Cite this article

Abstract

As technology advances to the point at which various behaviours of seven-transmembrane (7TM) receptors (also known as G protein-coupled receptors (GPCRs)) can be observed individually, it is clear that, rather than being 'on–off' switches, 7TM receptors are more akin to 'microprocessors' of information. This has introduced the phenomenon of functional selectivity, whereby certain ligands initiate only portions of the signalling mechanisms mediated by a given receptor, which has opened new horizons for drug discovery. The need to discover new 7TM receptor–ligand behaviours and quantify the effect of the drug on these complex systems, to guide medicinal chemistry, puts the pharmacological assay into the spotlight. This Perspective outlines the return to whole-system assays from reductionist recombinant systems, and discusses how the efficacy of a drug is linked to the particular assay used to observe its effects. It also highlights how these new assays are adding value to the drug discovery process.

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Figure 1: Quantification of drug activity through real-time observation of effect.
Figure 2: Receptor species monitored with different assay formats.
Figure 3: Increased texture of response with increased probes of receptor function.
Figure 4: The effect of cellular context on the responses to MAPK14 inhibitors.
Figure 5: Enhanced receptor desensitization assay through co-transfection with GRK2 and β-arrestin.

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  1. Terry P. Kenakin is at the Department of Biological Reagents and Assay Development, GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park, North Carolina 27709, USA. Terry.P.Kenakin@gsk.com,

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Kenakin, T. Cellular assays as portals to seven-transmembrane receptor-based drug discovery. Nat Rev Drug Discov 8, 617–626 (2009). https://doi.org/10.1038/nrd2838

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