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 D(2) receptor activation levels of bifeprunox and aripiprazole, two relatively similar dopamine D(2) 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 D(2) receptor antagonism in the rodent, aripiprazole would result in a higher D(2) receptor antagonism in the primate model. Furthermore, only the highest dose of aripiprazole, but not bifeprunox, reaches postsynaptic functional D(2) receptor antagonism similar to 4 mg haloperidol in the primate model. The model further identifies a limited optimal window of functionality for dopamine D(2) 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.