title: Aripiprazole's low intrinsic activities at human dopamine D2L and D2S receptors render it a unique antipsychotic.
abstract: Aripiprazole is the first clinically approved atypical antipsychotic agent having dopamine D2 receptor partial agonist activities. To evaluate aripiprazole's agonist and antagonist properties, we established a Chinese hamster ovary cell line expressing high and low densities of the long and short isoforms of human dopamine D2 receptors, then compared its properties with 7-{3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy}-2(1H)-quinolinone (OPC-4392), S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP), and terguride (other partial agonists) using forskolin-stimulated cAMP accumulation as an index. In cells expressing high receptor densities, all partial agonists predominantly behaved as agonists. However, in cells expressing low receptor densities, the partial agonists showed significantly lower maximal effects than dopamine. Aripiprazole showed the lowest intrinsic activities. In addition, all compounds blocked the action of dopamine with a maximum effect equal to that of each compound alone. Aripiprazole's low intrinsic activities may account for the clinical finding that, unlike the other partial agonists, it is substantially active against both positive and negative symptoms of schizophrenia.
authors.affiliation: Research Institute of Pharmacological and Therapeutical Development, Otsuka Pharmaceutical Co., Ltd., Tokushima 771-0192, Japan. y_tadori@research.otsuka.co.jp
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tadori
authors.forename: Takashi
authors.initials: T
authors.lastname: Miwa
authors.forename: Katsura
authors.initials: K
authors.lastname: Tottori
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Burris
authors.forename: Arlene
authors.initials: A
authors.lastname: Stark
authors.forename: Toyoki
authors.initials: T
authors.lastname: Mori
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kikuchi
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology; D000068180:Aripiprazole; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D018491:Dopamine Agonists / Q000378:metabolism / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology; D006220:Haloperidol / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008090:Lisuride / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology; D015363:Quinolones / Q000378:metabolism* / Q000494:pharmacology; D020891:Raclopride / Q000378:metabolism; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D018967:Risperidone / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014316:Tritium
chemical_list: D014150:Antipsychotic Agents; D018076:DNA, Complementary; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010879:Piperazines; D010880:Piperidines; D015363:Quinolones; D017448:Receptors, Dopamine D2; C113776:dopamine D2L receptor; D014316:Tritium; C054574:OPC 4392; D005576:Colforsin; C006208:dironyl; D020891:Raclopride; D000068180:Aripiprazole; C026539:preclamol; D000242:Cyclic AMP; D008090:Lisuride; D006220:Haloperidol; D018967:Risperidone; D004298:Dopamine