Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 597, Issue 1-3, Pages 27-33Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2008.09.008
Keywords
Aripiprazole; Antipsychotic; Dopamine D-3 receptor; Ser9Gly polymorphism; Schizophrenia; Partial agonist
Categories
Funding
- Otsuka Pharmaceutical Co., Ltd
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Aripiprazole is the first dopamine D-2/D-3 receptor partial agonist approved for use in the treatment of psychiatric disorders, including schizophrenia, bipolar disorder, and unipolar depression in the US. To explore the functional activity of aripiprazole at dopamine D-3 receptors, we established Chinese hamster ovary (CHO) cell lines stably expressing high and low densities of Ser-9 and Gly-9 variants of human cloparnine D-3 receptors and compared aripiprazole's cloparnine D-3 pharmacological properties with other marketed and non-approved dopamine D-3 receptor modulating agents on inhibition of forskolin-stimulated cAMP accumulation. Maximal cell responses for cloparnine were dependent on receptor expression levels, and all cells had similar potency for dopamine responses. Aripiprazole, terguride, bifeprunox, OPC-4392 (7-(3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy)-2(1H)-quinolinone), (-)-3-PPP ((-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine), SDZ 208-912 (N-[(8 alpha)-2-chloro-6-methylergolin-8-yl]-2,2-dimethylpropanamide), BP897 (N-[4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide) and GR103691 (4'-Acetyl-N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]biphenyl-4-carboxamide) behaved as partial agonists. Aripiprazole's intrinsic activity was similar to that of BP897 and GR103691, lower than that of terguride, bifeprunox, OPC-4392, and (-)-3-PPP, and higher than that of SDZ 208-912. The Gly-9 variant did not differ from the Ser-9 variant with respect to those agonist potencies and intrinsic activities. These compounds blocked the action of dopamine with a maximum effect equal to that of each compound alone. ACR16 (4-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine), quetiapine, clozapine, olanzapine, ziprasiclone, rispericlone, and haloperidol acted as antagonists. Aripiprazole's unique activity at cloparnine D3 receptors may translate into clinically relevant outcomes in patients with a variety of neuropsychiatric disorders. (C) 2008 Elsevier B.V. All rights reserved.
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