Not all partial dopamine D2 receptor agonists are the same in treating schizophrenia. Exploring the effects of bifeprunox and aripiprazole using a computer model of a primate striatal dopaminergic synapse

Original Research

(1332) Views  (405) Full article downloads

Authors: Athan Spiros, Robert Carr, Hugo Geerts

Published Date September 2010 Volume 2010:6(1) Pages 589 - 603

DOI: http://dx.doi.org/10.2147/NDT.S12460

Athan Spiros¹, Robert Carr¹, Hugo Geerts^1,2

¹In Silico Biosciences, Berwyn, PA, USA; ²School of Medicine, University of Pennsylvania, PA, USA

Abstract: Species differences in physiology and unique active human metabolites contribute to the limited predictive value of preclinical rodent models for many central nervous system (CNS) drugs. In order to explore possible drivers for this translational disconnect, we developed a computer model of a dopaminergic synapse that simulates the competition among three agents and their binding to pre- and postsynaptic receptors, based on the affinities for their targets and their actual concentrations. The model includes presynaptic autoreceptor effects on neurotransmitter release and modulation by presynaptic firing frequency and is calibrated with actual experimental data on free dopamine levels in the striatum of the rodent and the primate. Using this model, we simulated the postsynaptic dopamine D₂ receptor activation levels of bifeprunox and aripiprazole, two relatively similar dopamine D₂ receptor agonists. The results indicate a substantial difference in dose–response for the two compounds when applying primate calibration parameters as opposed to rodent calibration parameters. In addition, when introducing the major human and rodent metabolites of aripiprazole with their specific pharmacological activities, the model predicts that while bifeprunox would result in a higher postsynaptic D₂ receptor antagonism in the rodent, aripiprazole would result in a higher D₂ receptor antagonism in the primate model. Furthermore, only the highest dose of aripiprazole, but not bifeprunox, reaches postsynaptic functional D₂ receptor antagonism similar to 4 mg haloperidol in the primate model. The model further identifies a limited optimal window of functionality for dopamine D₂ receptor partial agonists. These results suggest that computer modeling of key CNS processes, using well-validated calibration paradigms, can increase the predictive value in the clinical setting of preclinical animal model outcomes.

Keywords: dopamine antagonism, partial agonist, antipsychotics, computer simulation