Aripiprazole is the first next-generation atypical antipsychotic with a mechanism of action that differs from currently marketed typical and atypical antipsychotics. Aripiprazole displays properties of an agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity, respectively. This study examined the interactions of aripiprazole with a single population of human D2 receptors to clarify further its pharmacologic properties. In membranes prepared from Chinese hamster ovary cells that express recombinant D2L receptors, aripiprazole bound with high affinity to both the G protein-coupled and uncoupled states of receptors. Aripiprazole potently activated D2 receptor-mediated inhibition of cAMP accumulation. Partial receptor inactivation using the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) significantly reduced the maximum effect of aripiprazole on inhibition of cAMP accumulation. This effect was seen with concentrations of EEDQ that did not alter the maximal inhibitory effect of dopamine. Consistent with the expected effects of a partial agonist, increasing concentrations of aripiprazole blocked the action of dopamine with maximal blockade equal to the agonist effect of aripiprazole alone. The efficacy of aripiprazole relative to that of dopamine varied from 25% in cells that lacked spare receptors for dopamine to 90% in cells with receptor reserve. These results, together with previous studies demonstrating partial agonist activity at serotonin 5-hydroxytryptamine (5-HT)1A receptors and antagonist activity at 5-HT2A receptors, support the identification of aripiprazole as a dopamine-serotonin system stabilizer. The receptor activity profile may underlie the unique activity of aripiprazole in animals and its antipsychotic activity in humans.

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To develop a novel antipsychotic agent which is an agonist of dopamine (DA) autoreceptors and an antagonist of postsynaptic DA receptors, a series of 7-[4-[4-(substituted phenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2 (1H)-quinolinones was synthesized and their dual activities were examined. The postsynaptic DA receptor antagonistic activities of the compounds were evaluated by their ability to inhibit stereotypy induced by apomorphine in mice, and the autoreceptor agonist activities were determined by their effects on the gamma-butyrolactone (GBL)-induced increase in L-dihydroxyphenylalanine (DOPA) synthesis in the mouse brain. Many compounds inhibited the stereotypic behavior, and several compounds reversed the GBL-induced increase in the DOPA synthesis. Among them, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy]-3,4-dihydro-2 (1H)-quinolinone (28, aripiprazole, OPC-14597) was found to have these two activities. This compound reversed the GBL-induced DOPA synthesis (ED50 values of 5.1 mumol/kg p.o.) and inhibited the APO induced stereotypy (ED50 values of 0.6 mumol/kg p.o.). Compound 28 induced catalepsy at 10 times higher dose than that required for the antagonism of APO-induced stereotypy (ED50 value of 7.8 mumol/kg p.o.).

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