GPCR functional selectivity has therapeutic impact

Many in vitro data show that some ligands can cause the differential activation of signaling pathways mediated by a single receptor (termed 'functional selectivity'). It remains unclear, however, whether functionally selective properties are meaningful in vivo. Data obtained with experimental compounds that are functionally selective at the dopamine D(2L) receptor in vitro suggest that these properties might predict atypical behavioral actions. Moreover, the antipsychotic drug aripiprazole is commonly thought to be a D(2) partial agonist, but data clearly show that aripiprazole is functionally selective in vitro. It is proposed that the effects of aripiprazole in animal models and humans can be reconciled only with its functionally selective D(2) properties, not its partial D(2) agonism. Together, these data provide support for the hypothesis that compounds with functionally selective properties in vitro are likely to have novel actions in vivo, opening doors to new avenues of drug discovery.