title: Aripiprazole and its human metabolite are partial agonists at the human dopamine D2 receptor, but the rodent metabolite displays antagonist properties.
abstract: Aripiprazole is a novel antipsychotic drug, which displays partial agonist activity at the dopamine D(2) receptor. Aripiprazole has been extensively studied pre-clinically, both in vitro and in vivo, and these results have been correlated with clinical findings. However, aripiprazole is metabolised differently in rats and man and these metabolites may contribute to the profile of aripiprazole observed in vivo. We have therefore studied the interaction of aripiprazole and its principal rat and human metabolites in both in vitro models of dopamine hD(2) receptor function and affinity, and of in vivo models of dopamine rat D(2) receptor function. The human metabolite displayed similar levels of partial agonist activity to aripiprazole at the dopamine hD(2) receptor and displayed similar behavioural profile to aripiprazole in vivo, suggesting that in man the metabolite may maintain the effects of aripiprazole. In contrast, the rat metabolite displayed antagonist activity both in vitro and in vivo. Thus care must be taken in ascribing effects seen in vivo with aripiprazole in rats to dopamine D(2) receptor partial agonist activity in man, and that care must also be taken in extrapolating effects seen in rats to man, particularly from long-term studies.
authors.affiliation: Psychiatry Centre for Excellence in Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. martyn.wood@gsk.com
authors.forename: Martyn D
authors.initials: MD
authors.lastname: Wood
authors.forename: Claire
authors.initials: C
authors.lastname: Scott
authors.forename: Kirsten
authors.initials: K
authors.lastname: Clarke
authors.forename: Julie
authors.initials: J
authors.lastname: Westaway
authors.forename: Ceri H
authors.initials: CH
authors.lastname: Davies
authors.forename: Charlie
authors.initials: C
authors.lastname: Reavill
authors.forename: Mark
authors.initials: M
authors.lastname: Hill
authors.forename: Claire
authors.initials: C
authors.lastname: Rourke
authors.forename: Michael
authors.initials: M
authors.lastname: Newson
authors.forename: Declan N C
authors.initials: DN
authors.lastname: Jones
authors.forename: Ian T
authors.initials: IT
authors.lastname: Forbes
authors.forename: Andrew
authors.initials: A
authors.lastname: Gribble
mesh_terms: D000661:Amphetamine; D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000068180:Aripiprazole; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive; D001711:Biotransformation; D016466:CHO Cells; D002375:Catalepsy / Q000139:chemically induced; D006224:Cricetinae; D003412:Cricetulus; D065127:Dopamine D2 Receptor Antagonists; D004409:Dyskinesia, Drug-Induced / Q000209:etiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D015363:Quinolones / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D013045:Species Specificity; D014162:Transfection
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; C504128:OPC-14857; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000068180:Aripiprazole; D016627:Oxidopamine; D000661:Amphetamine