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In vitro functional characteristics of dopamine D2 receptor partial agonists in second and third messenger-based assays of cloned human dopamine D2Long receptor signallingDepartment of Neuroscience Research, Otsuka Maryland Medicinal Laboratories, Rockville, MD, USA, shaunj{at}otsuka.com
Department of Neuroscience Research, Otsuka Maryland Medicinal Laboratories, Rockville, MD, USA
Department of Neuroscience Research, Otsuka Maryland Medicinal Laboratories, Rockville, MD, USA
Department of Neuroscience Research, Otsuka Maryland Medicinal Laboratories, Rockville, MD, USA
Department of Neuroscience Research, Otsuka Maryland Medicinal Laboratories, Rockville, MD, USA
Otsuka Abilify Unit, Princeton, NJ, USA
Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd, Kawauchi-cho, Tokushima, Japan
Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd, Kawauchi-cho, Tokushima, Japan
Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd, Kawauchi-cho, Tokushima, Japan Aripiprazole, (+)terguride, OPC-4392 and (—)3-PPP have been classified as dopamine D2 receptor partial agonists based largely on their activity in second messenger-based assays of dopamine D2 receptor signalling. Nevertheless, signal transduction amplification might result in these compounds behaving as dopamine D2 receptor full agonists at a more downstream level of signalling. We compared the intrinsic activity (Emax, expressed as a percentage of the maximal effect of dopamine) of aripiprazole, (+)terguride, OPC-4392 and (—)3-PPP using second (calcium (Ca2+) mobilization) and third (extracellular signal-regulated kinase 2 (ERK2) phosphoprotein expression) messenger readouts of cloned human dopamine D2long (hD2L) receptor signalling in CHO cells. These compounds were all less potent and displayed lower intrinsic activity in the Ca2+ assay (aripiprazole = 24.3%, (+)terguride = 56.9%, OPC-4392 = 58.6% and (—)3-PPP = 75.1%), and aripiprazole (Emax = 54.5%) displayed a substantially lower intrinsic activity than (+)terguride (Emax = 92.3%), OPC-4392 (Emax = 93.1%) and (—)3-PPP (Emax = 101.1%) in the more downstream-based ERK2 phosphoprotein expression assay. These drug effects on Ca2+ mobilization and ERK2 phosphoprotein expression were mediated through dopamine hD2L receptors, as they all were blocked by (—)raclopride, whereas (—)raclopride and other dopamine D2 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 D2 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 D2 receptor partial agonist therapeutics.
Key Words: aripiprazole (OPC-14597) • partial agonist • schizophrenia • dopamine • confocal
This version was published on August
1, 2007 Journal of Psychopharmacology, Vol. 21, No. 6,
620-627 (2007) |
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