In vitro functional characteristics of dopamine D₂ receptor partial agonists in second and third messenger-based assays of cloned human dopamine D_2Long receptor signalling

¹ Department of Neuroscience Research, Otsuka Maryland Medicinal Laboratories, Rockville, MD, USA.
² Otsuka Abilify® Unit, Princeton, NJ, USA.
³ Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd, Kawauchi-cho, Tokushima, Japan.

^* To whom correspondence should be addressed.

	Abstract

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 (E_max, 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 D_2Long (hD_2L) 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 (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 Ca²⁺ mobilization and ERK2 phosphoprotein expression were mediated through dopamine hD_2L 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

First published on November 8, 2006, doi:10.1177/0269881106072090

Journal of Psychopharmacology 2007;21:620.

A more recent version of this article appeared on August 1, 2007


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