title: The novel antipsychotic aripiprazole is a partial agonist at short and long isoforms of D2 receptors linked to the regulation of adenylyl cyclase activity and prolactin release.
abstract: Aripiprazole is a novel antipsychotic with a unique mechanism of action, which differs from currently marketed typical and atypical antipsychotics. Aripiprazole has been shown to be a partial agonist at the D(2) family of dopamine (DA) receptors in biochemical and pharmacological studies. To demonstrate aripiprazole's action as a partial D(2) agonist in pituitary cells at the molecular level, we retrovirally transduced the short (D(2S)) and the long (D(2L)) form of the human DA D(2) receptor gene into a rat pituitary cell line, GH4C1. [(3)H]-raclopride saturation binding analyses revealed a B(max) value approximately four-fold higher at D(2S) receptor-expressing GH4C1 cells than at D(2L) receptor-expressing GH4C1 cells, while a K(d) value was similar. Aripiprazole inhibited forskolin-stimulated release of prolactin in both D(2S) and D(2L) receptor-expressing GH4C1 cells, whereas the maximal inhibition of prolactin release was less than that of DA. Similarly, aripiprazole partially inhibited forskolin-induced cAMP accumulation in both D(2) receptor-expressing cells. Aripiprazole antagonized the suppression attained by DA (10(-7) M) in both D(2) receptor-expressing cells and, at the maximal blockade of cAMP, yielded residual cAMP levels equal to those produced by aripiprazole alone. These results indicate that aripiprazole acts as a partial agonist at both D(2S) and D(2L) receptors expressed in GH4C1 cells. These data may explain, at least in part, the observations that aripiprazole shows a novel antipsychotic activity with minimal potential for adverse events including no significant increase of serum prolactin levels in clinical studies.
authors.affiliation: Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co, Ltd, 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan. k_aihara@research.otsuka.co.jp
authors.forename: Koutoku
authors.initials: K
authors.lastname: Aihara
authors.forename: Jun
authors.initials: J
authors.lastname: Shimada
authors.forename: Takashi
authors.initials: T
authors.lastname: Miwa
authors.forename: Katsura
authors.initials: K
authors.lastname: Tottori
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Burris
authors.forename: Frank D
authors.initials: FD
authors.lastname: Yocca
authors.forename: Masato
authors.initials: M
authors.lastname: Horie
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kikuchi
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D002460:Cell Line; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D011388:Prolactin / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D020033:Protein Isoforms / Q000819:agonists / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D010879:Piperazines; D020033:Protein Isoforms; D015363:Quinolones; D017448:Receptors, Dopamine D2; D000068180:Aripiprazole; D011388:Prolactin; D000262:Adenylyl Cyclases