title: Dopamine D2 receptor partial agonists display differential or contrasting characteristics in membrane and cell-based assays of dopamine D2 receptor signaling.
abstract: Clinical evidence suggests that dopamine D(2) receptor partial agonists must have a sufficiently low intrinsic activity to be effective as antipsychotics. Here, we used dopamine D(2) receptor signaling assays to compare the in vitro functional characteristics of the antipsychotic aripiprazole with other dopamine D(2) receptor partial agonists (7-{3-[4-(2,3-dimethylphenyl)-piperazinyl]propoxy}-2(1H)-quinolinone [OPC-4392], (-)-3-(3-hydroxy-phenyl)-N-n-propylpiperidine [(-)3-PPP] and (+)terguride) and dopamine D(2) receptor antagonists. Aripiprazole and OPC-4392 were inactive in a guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTPgammaS) binding assay using Chinese Hamster Ovary (CHO) cell membranes expressing cloned human dopamine D(2Long) (hD(2L)) receptors, whereas (-)3-PPP and (+)terguride displayed low intrinsic activity. Aripiprazole also had no effect on [(35)S]GTPgammaS binding to CHO-hD(2L) cells, while OPC-4392, (-)3-PPP and (+)terguride were partial agonists. In contrast, aripiprazole, OPC-4392, (-)3-PPP, and (+)terguride were inactive in a [(35)S]GTPgammaS binding assay using rat striatal membranes. However, at a more downstream level of CHO-hD(2L) cell signalling, these drugs all behaved as dopamine hD(2L) receptor partial agonists, with aripiprazole displaying an intrinsic activity 2 to 3-fold lower (inhibition of forskolin-induced adenosine 3',5'-cyclic monophosphate accumulation) and almost half as high (enhancement of adenosine triphosphate-stimulated [(3)H]arachidonic acid release) as OPC-4392, (-)3-PPP and (+)terguride. Dopamine activity was blocked in each case by (-)raclopride, which was inactive on its own in every assay, as were the antipsychotics haloperidol, olanzapine, ziprasidone and clozapine. Together, these data, whilst preclinical in nature, are consistent with clinical evidence suggesting the favorable antipsychotic profile of aripiprazole, compared with the other clinically ineffective partial agonists, is dependent on its low intrinsic activity at dopamine D(2) receptors. This study also highlights the limitations of using [(35)S]GTPgammaS binding assays to identify dopamine D(2) receptor partial agonists.
authors.affiliation: Department of Neuroscience Research, Otsuka Maryland Medicinal Laboratories, 9900 Medical Center Drive, Rockville, MD 20850, USA. Shaun.Jordan@otsuka.com
authors.forename: Shaun
authors.initials: S
authors.lastname: Jordan
authors.forename: Janelle L
authors.initials: JL
authors.lastname: Johnson
authors.forename: Karen
authors.initials: K
authors.lastname: Regardie
authors.forename: Ruoyan
authors.initials: R
authors.lastname: Chen
authors.forename: Vuk
authors.initials: V
authors.lastname: Koprivica
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tadori
authors.forename: Junichi
authors.initials: J
authors.lastname: Kambayashi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kikuchi
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001667:Binding, Competitive; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D009474:Neurons / Q000166:cytology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D014162:Transfection / Q000379:methods
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D013460:Sulfur Isotopes; D016718:Arachidonic Acid; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP