PT  - JOURNAL ARTICLE
AU  - Kevin D. Burris
AU  - Thaddeus F. Molski
AU  - Cen Xu
AU  - Elaine Ryan
AU  - Katsura Tottori
AU  - Tetsuro Kikuchi
AU  - Frank D. Yocca
AU  - Perry B. Molinoff
TI  - Aripiprazole, a Novel Antipsychotic, Is a High-Affinity Partial Agonist at Human Dopamine D2 Receptors
AID  - 10.1124/jpet.102.033175
DP  - 2002 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 381--389
VI  - 302
IP  - 1
4099  - http://jpet.aspetjournals.org/content/302/1/381.short
4100  - http://jpet.aspetjournals.org/content/302/1/381.full
SO  - J Pharmacol Exp Ther2002 Jul 01; 302
AB  - 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 agentN-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. The American Society for Pharmacology and Experimental Therapeutics