Ligand functional selectivity advances our understanding of drug mechanisms and drug discovery.

‘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. The question is whether functional selectivity is an interesting artifact for the specialist, or a mechanism that affects psychoactive drug action and drug discovery. The data suggest that both are true (Kilts et al, 2002; Smith et al, 1997). As an example, a recent publication examined the impact of functional selectivity on valvulopathy, which was thought to be due to 5-HT2B agonist-induced mitogenic action in the heart. Clinical drugs were selected for their 5-HT2B agonist profile in traditional assays, and then functionally profiled. Of this group, ropinirole was differentiated from the other compounds by its signaling profile, possibly explaining why it has a decreased risk of valvulopathy (Huang et al, 2009). To our knowledge, this is the first example for the differentiated side-effect profiles of functional selectivity. Of direct neuropsychopharmacological relevance is the dopamine mechanism of action of aripiprazole. The most commonly disseminated hypothesis is that aripiprazole causes ‘dopamine stabilization' through D2 partial agonism. Conversely, other data have shown that aripiprazole, although sometimes a partial agonist, can also be a D2 pure antagonist or full agonist depending on the assay system. As we have reviewed recently (Mailman, 2007), the original in vivo/ex vivo data from the drug's discoverers are consistent with D2 functional selectivity, but not with simple partial agonism. Functional selectivity would thus predict that D2 ligands selected as partial agonists in a single common functional assay may not be similar clinically. From this perspective, the failure of preclamol or bifeprunox to have adequate antipsychotic efficacy may not be surprising. The level of complexity added by functional selectivity also provides opportunity. In the short term, it permits a greater understanding of the differential neuropsychopharmacology of drugs once thought to be functionally similar, and may permit discrimination of potential drug candidates. In the long term, scientific advances showing how individual signaling pathways affect cellular function (and subsequent physiological responses) will provide a mechanistic foundation for the discovery of rationally chosen functionally selective drugs.