GPCR functional selectivity has therapeutic impact

Abstract

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 D2L receptor in vitro suggest that these properties might predict atypical behavioral actions. Moreover, the antipsychotic drug aripiprazole is commonly thought to be a D2 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 D2 properties, not its partial D2 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.

Figure 1

Ligand-receptor interactions can cause functional selectivity that is expressed in several ways. The potency of ligands can be differentially affected when two different receptor-mediated assays are conducted in the same cell line (left panel). The relative potency of aripiprazole in two functional assays differs by more than two orders of magnitude, unlike dopamine or other dopamine agonists. In addition, a ligand may cause discrete differences in intrinsic activity (right side). PropylDHX is a full agonist at D_2L mediated inhibition of adenylate cyclase (top right panel), yet is an antagonist at D_2L-mediated inhibition of dopamine release (bottom right panel). Conversely, quinpirole affects both functions similarly. Data originally from Kilts et al. [33] and Urban et al. [34]

Figure 2

How a functionally selective drug might decrease side effects. In this hypothetical example, effects on GIRK channels are linked to a side effect, whereas effects on adenylate cyclase are linked to therapeutic effects. The functionally selective drug (left panel) has actions primarily on adenylate cyclase, whereas the typical agonist (right panel) has effects on both pathways. Thus, the functionally selective drug would have a better therapeutic index. This cartoon shows the polar extremes (pure agonism vs pure antagonism for the functionally selective drugs). In practice, a useful functionally selective ligand might have different degrees of partial intrinsic activity (not resulting from differences in receptor reserve!) at two (or more) key transduction mechanisms.