In vitro pharmacology of aripiprazole, its metabolite and experimental dopamine partial agonists at human dopamine D2 and D3 receptors

Eur J Pharmacol. 2011 Oct 15;668(3):355-65. doi: 10.1016/j.ejphar.2011.07.020. Epub 2011 Jul 29.


Aripiprazole is the first dopamine D(2)/D(3) receptor partial agonist successfully developed and ultimately approved for treatment of a broad spectrum of psychiatric and neurological disorders. Aripiprazole's dopamine D(2) and serotonin 5-HT(1A) receptor partial agonist activities have been postulated to confer clinical efficacy without marked sedation, and a relatively favorable overall side-effect profile. Using aripiprazole's unique profile as a benchmark for new dopamine partial agonist development may facilitate discovery of new antipsychotics. We conducted an in vitro comparative analysis between aripiprazole, and its human metabolite OPC-14857 (7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl)butoxy)-2(1H)-quinolinone)); RGH-188 (trans-1-[4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl]-3,3-dimethylurea), and its metabolite didesmethyl-RGH-188 (DDM-RGH-188); as well as bifeprunox, sarizotan, N-desmethylclozapine (NDMC; clozapine metabolite), and SDZ 208-912 (N-[(8α)-2-chloro-6-methylergolin-8-yl]-2,2-dimethylpropanamide). In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cell lines expressing D(2S), D(2L), D(3) Ser-9 and D(3) Gly-9 for human dopamine receptors. All test compounds behaved as dopamine D(2)/D(3) receptor partial agonists. Aripiprazole's intrinsic activity at dopamine D(2S) and D(2L) receptors was similar to that of OPC-14857 and RGH-188; lower than that of dopamine and bifeprunox; and higher than that of DDM-RGH-188, SDZ 208-912, sarizotan, and NDMC. Aripiprazole's intrinsic activity at dopamine D(3) Ser-9 and D(3) Gly-9 receptors was similar to that of OPC-14857 and sarizotan; lower than that of dopamine, bifeprunox, RGH-188 and DDM-RGH-188; and higher than that of SDZ 208-912 and NDMC. A consolidated assessment of these findings may help defining the most appropriate magnitude of intrinsic activity at dopamine D(2)/D(3) receptors for clinical efficacy and safety.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aripiprazole
  • CHO Cells
  • Clozapine / metabolism
  • Clozapine / pharmacology
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / metabolism
  • Dopamine / metabolism*
  • Drug Partial Agonism*
  • Humans
  • Organic Chemicals / metabolism
  • Organic Chemicals / pharmacology
  • Piperazines / metabolism*
  • Piperazines / pharmacology*
  • Quinolones / metabolism*
  • Quinolones / pharmacology*
  • Receptors, Dopamine D2 / agonists*
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Dopamine D3 / agonists*
  • Receptors, Dopamine D3 / metabolism
  • Substrate Specificity


  • OPC-14857
  • Organic Chemicals
  • Piperazines
  • Quinolones
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • dopamine D2L receptor
  • sarizotan
  • Aripiprazole
  • Cyclic AMP
  • cariprazine
  • Clozapine
  • Dopamine