title: 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.affiliation: Quests Research Institute, 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: Robert A
authors.initials: RA
authors.lastname: Forbes
authors.forename: Robert D
authors.initials: RD
authors.lastname: McQuade
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kikuchi
mesh_terms: D000818:Animals; D000068180:Aripiprazole; D016466:CHO Cells; D003024:Clozapine / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D054333:Drug Partial Agonism; D006801:Humans; D009930:Organic Chemicals / Q000378:metabolism / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology*; D015363:Quinolones / Q000378:metabolism* / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: C504128:OPC-14857; D009930:Organic Chemicals; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C113776:dopamine D2L receptor; C443959:sarizotan; D000068180:Aripiprazole; D000242:Cyclic AMP; C533287:cariprazine; D003024:Clozapine; D004298:Dopamine