Atypical antipsychotic drugs have revolutionized the treatment of schizophrenia and related disorders. The current clinically approved atypical antipsychotic drugs are characterized by having relatively low affinities for D 2 -dopamine receptors and relatively high affinities for 5-HT 2A serotonin receptors (5-HT, 5-hydroxytryptamine (serotonin)). Aripiprazole (OPC-14597) is a novel atypical antipsychotic drug that is reported to be a high-affinity D 2 -dopamine receptor partial agonist. We now provide a comprehensive pharmacological profile of aripiprazole at a large number of cloned G protein-coupled receptors, transporters, and ion channels. These data reveal a number of interesting and potentially important molecular targets for which aripiprazole has affinity. Aripiprazole has highest affinity for h5-HT 2B -, hD 2L -, and hD 3 -dopamine receptors, but also has significant affinity

D 2 -like dopamine receptors mediate functional changes via activation of inhibitory G proteins, including those that affect adenylate cyclase activity, and potassium and calcium channels. Although it is assumed that the binding of a drug to a single isoform of a D 2 -like receptor will cause similar changes in all receptor-mediated functions, it has been demonstrated in brain that the dopamine agonists dihydrexidine (DHX) and N-npropyl-DHX are "functionally selective". The current study explores the underlying mechanism using transfected MN9D cells and D 2 -producing anterior pituitary lactotrophs. Both dopamine and DHX inhibited adenylate cyclase activity in a concentrationdependent manner in both systems, effects blocked by D 2 , but not D 1 , antagonists. In the MN9D cells, quinpirole and R-(Ϫ)-N-propylnorapomorphine (NPA) also inhibited the K ϩ -stimulated release of [ 3 H]dopamine in a concentration-responsive, antagonist-reversible manner. Conversely, neither DHX, nor its analogs, inhibited K ϩ -stimulated [ 3 H]dopamine release, although they antagonized the effects of quinpirole. S-(ϩ)-NPA actually had the reverse functional selectivity profile from DHX (i.e., it was a full agonist at D 2L receptors coupled to inhibition of dopamine release, but a weak partial agonist at D 2L receptormediated inhibition of adenylate cyclase). In lactotrophs, DHX had little intrinsic activity at D 2 receptors coupled to G proteincoupled inwardly rectifying potassium channels, and actually antagonized the effects of dopamine at these D 2 receptors. Together, these findings provide compelling evidence for agonist-induced functional selectivity with the D 2L receptor. Although the underlying molecular mechanism is controversial (e.g., "conformational induction" versus "drug-active state selection"), such data are irreconcilable with the widely held view that drugs have "intrinsic efficacy".The dopamine receptors, members of the G protein-coupled receptor superfamily, are generally divided into two classes, "D 1 -like" and "D 2 -like" (Jaber et al., 1996;Huff, 1997) In the central nervous system, dopamine receptors exist on both dopamine neurons (on soma, dendrites, and terminals) and postsynaptically on target cells. Presynaptic receptors (autoreceptors) fall under the D 2 -like class of dopamine re-