title: In vitro functional characteristics of dopamine D2 receptor partial agonists in second and third messenger-based assays of cloned human dopamine D2Long receptor signalling.
abstract: Aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP have been classified as dopamine D(2) receptor partial agonists based largely on their activity in second messenger-based assays of dopamine D(2) receptor signalling. Nevertheless, signal transduction amplification might result in these compounds behaving as dopamine D(2) receptor full agonists at a more downstream level of signalling. We compared the intrinsic activity (E(max), expressed as a percentage of the maximal effect of dopamine) of aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP using second (calcium (Ca(2+)) mobilization) and third (extracellular signal-regulated kinase 2 (ERK2) phosphoprotein expression) messenger readouts of cloned human dopamine D(2long) (hD(2L)) receptor signalling in CHO cells. These compounds were all less potent and displayed lower intrinsic activity in the Ca(2+) assay (aripiprazole = 24.3%, (+)terguride = 56.9%, OPC-4392 = 58.6% and (-)3-PPP = 75.1%), and aripiprazole (E(max) = 54.5%) displayed a substantially lower intrinsic activity than (+)terguride (E(max) = 92.3%), OPC-4392 (E(max) = 93.1%) and (-)3-PPP (E(max) = 101.1%) in the more downstream-based ERK2 phosphoprotein expression assay. These drug effects on Ca(2+) mobilization and ERK2 phosphoprotein expression were mediated through dopamine hD(2L) receptors, as they all were blocked by (-)raclopride, whereas (-)raclopride and other dopamine D(2) receptor antagonists (haloperidol, risperidone, ziprasidone, olanzapine, clozapine and quetiapine) were inactive on their own in both assays. These data are consistent with clinical evidence that only dopamine D(2) receptor partial agonists with a sufficiently low enough intrinsic activity will prove effective against the positive symptoms of schizophrenia, and also highlight the importance of using downstream-based assays in the discovery of novel D(2) receptor partial agonist therapeutics.
authors.affiliation: Department of Neuroscience Research, Otsuka Maryland Medicinal Laboratories, 9900 Medical Center Drive, Rockville, MD 20850, USA. shaunj@otsuka.com
authors.forename: Shaun
authors.initials: S
authors.lastname: Jordan
authors.forename: Karen
authors.initials: K
authors.lastname: Regardie
authors.forename: Janelle L
authors.initials: JL
authors.lastname: Johnson
authors.forename: Ruoyan
authors.initials: R
authors.lastname: Chen
authors.forename: Junichi
authors.initials: J
authors.lastname: Kambayashi
authors.forename: Robert
authors.initials: R
authors.lastname: McQuade
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tadori
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kikuchi
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000068180:Aripiprazole; D016466:CHO Cells; D020013:Calcium Signaling / Q000187:drug effects*; D003001:Cloning, Molecular; D006224:Cricetinae; D003412:Cricetulus; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D015151:Immunoblotting; D008090:Lisuride / Q000031:analogs & derivatives / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D018613:Microscopy, Confocal; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D020891:Raclopride / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010879:Piperazines; D010880:Piperidines; D015363:Quinolones; D017448:Receptors, Dopamine D2; C113776:dopamine D2L receptor; C054574:OPC 4392; C006208:dironyl; D020891:Raclopride; D000068180:Aripiprazole; C026539:preclamol; D008090:Lisuride; D019950:Mitogen-Activated Protein Kinase 1; D004298:Dopamine