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

Abstract

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.

• Authors: Yoshihiro Tadori, Robert A Forbes, Robert D McQuade, Tetsuro Kikuchi
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 668 Issue 3 Pg. 355-65 (Oct 15 2011) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 21816144 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

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

Topics

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