Blog
About

2
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Not all partial dopamine D 2 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

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Author and article information

          Journal
          Neuropsychiatr Dis Treat
          Neuropsychiatric Disease and Treatment
          Neuropsychiatric Disease and Treatment
          Dove Medical Press
          1176-6328
          1178-2021
          7 September 2010
          2010
          2010
          : 6
          : 589-603
          Affiliations
          [1 ] In Silico Biosciences, Berwyn, PA, USA
          [2 ] School of Medicine, University of Pennsylvania, PA, USA
          Author notes
          Correspondence: Hugo Geerts, In Silico Biosciences, Inc, 686 Westwind, Berwyn, PA 19312, USA, Tel +1 267 679 8090, Fax +1 781 862 7690, Email hugo-geerts@ 123456in-silicobiosciences.com
          Article
          ndt-6-589
          10.2147/NDT.S12460
          2938308
          20856922
          © 2010 Spiros et al, publisher and licensee Dove Medical Press Ltd.

          This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

          Categories
          Original Research

          Neurology

          dopamine antagonism, computer simulation, partial agonist, antipsychotics

          Comments

          Comment on this article