In recent years, it has become evident that drug actions at GPCRs is more complex than simply promoting or disrupting the receptors coupling to a cognate G protein. Moreover, it has become evident that GPCRs can signal through multiple G proteins and even independent of G proteins, such as through beta arrestins, to promote biological responses. It is also clear that the chemical nature of the ligand can drive selective coupling between GPCRs and their effectors; a phenomenon which opens a chemistry landscape for potentially fine-tuning of receptor signaling towards preferential effects and away from �side effects�. This presentation will focus on demonstrating functional selectivity of GPCR signaling in vivo and a discussion of certain considerations that must be taken into account when using cell-based systems to model biased agonism for drug discovery.

Seeking ligand bias: Assessing GPCR coupling to beta arrestins for drug discovery

243rd National Meeting (2012)

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