Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology

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 D₂-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 D₂-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 hD₃- dopamine receptors, but also has significant affinity (5-30 nM) for several other 5-HT receptors (5-HT_1A, 5-HT_2A, 5-HT₇), as well as α_1A-adrenergic and hH₁-histamine receptors. Aripiprazole has less affinity (30-200 nM) for other G protein-coupled receptors, including the 5-HT_1D, 5-HT_2C, α_1B-, α_2A-, α_2B-, α_2C-, β₁-, and β₂-adrenergic, and H₃-histamine receptors. Functionally, aripiprazole is an inverse agonist at 5-HT_2B receptors and displays partial agonist actions at 5-HT_2A, 5-HT_2C, D₃, and D₄ receptors. Interestingly, we also discovered that the functional actions of aripiprazole at cloned human D₂-dopamine receptors are cell-type selective, and that a range of actions (eg agonism, partial agonism, antagonism) at cloned D₂-dopamine receptors are possible depending upon the cell type and function examined. This mixture of functional actions at D ₂-dopamine receptors is consistent with the hypothesis proposed by Lawler et al (1999) that aripiprazole has 'functionally selective' actions. Taken together, our results support the hypothesis that the unique actions of aripiprazole in humans are likely a combination of 'functionally selective' activation of D₂ (and possibly D₃)-dopamine receptors, coupled with important interactions with selected other biogenic amine receptors - particularly 5-HT receptor subtypes (5-HT_1A, 5-HT_2A).