‘Intrinsic efficacy’ (the concept that a drug acting at a single receptor is always an agonist, partial agonist, or antagonist/inverse agonist) had been accepted for a half-century. Two decades ago, it became clear that a single G protein-coupled receptor (GPCR) could have promiscuous G protein interactions. This suggested that some drugs might cause differential effects on signaling via a single receptor, and within a few years, there were data showing such ‘anomalous’ functional responses—in the extreme, a ligand acting at a single receptor being a full agonist at one function and an antagonist at another (Kilts et al, 2002).

Strikingly, most laboratories engaged with this phenomenon recognized its implications, each proffering a unique name (eg, agonist-directed trafficking of signaling, biased agonism, etc), with functional selectivity emerging as the apparent consensus. The naming quandary, the involved mechanisms, the impact on understanding drug action, the relevance to drug discovery, and even the implications for teaching have been reviewed recently (Urban et al, 2007), now including the first book on the subject (Neve, 2009). It appears that this is a universal phenomenon for all GPCRs and other drug targets, and that many drugs may cause such differential signaling.

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