Characterization of aripiprazole partial agonist activity at human dopamine D3 receptors

Eur J Pharmacol. 2008 Nov 12;597(1-3):27-33. doi: 10.1016/j.ejphar.2008.09.008. Epub 2008 Sep 20.


Aripiprazole is the first dopamine D2/D3 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 D3 receptors, we established Chinese hamster ovary (CHO) cell lines stably expressing high and low densities of Ser-9 and Gly-9 variants of human dopamine D3 receptors and compared aripiprazole's dopamine D3 pharmacological properties with other marketed and non-approved dopamine D3 receptor modulating agents on inhibition of forskolin-stimulated cAMP accumulation. Maximal cell responses for dopamine 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, ziprasidone, risperidone, and haloperidol acted as antagonists. Aripiprazole's unique activity at dopamine D3 receptors may translate into clinically relevant outcomes in patients with a variety of neuropsychiatric disorders.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / metabolism
  • Antipsychotic Agents / pharmacology*
  • Aripiprazole
  • Binding, Competitive
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / metabolism
  • Dopamine Agonists / metabolism
  • Dopamine Agonists / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Partial Agonism
  • Humans
  • Mutation
  • Piperazines / metabolism
  • Piperazines / pharmacology*
  • Quinolones / metabolism
  • Quinolones / pharmacology*
  • Radioligand Assay
  • Receptors, Dopamine D3 / agonists*
  • Receptors, Dopamine D3 / genetics
  • Receptors, Dopamine D3 / metabolism
  • Tetrahydronaphthalenes / metabolism
  • Transfection


  • Antipsychotic Agents
  • DRD3 protein, human
  • Dopamine Agonists
  • Piperazines
  • Quinolones
  • Receptors, Dopamine D3
  • Tetrahydronaphthalenes
  • Aripiprazole
  • Cyclic AMP
  • 7-hydroxy-2-N,N-dipropylaminotetralin