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

Athan Spiros1, Robert Carr1, Hugo Geerts1,21In Silico Biosciences, Berwyn, PA, USA; 2School of Medicine, University of Pennsylvania, PA, USAAbstract: Species differences in physiology and unique active human metabolites contribute to the limited predictive value of preclinical rodent models for many...

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Autores principales:	Athan Spiros, Robert Carr, Hugo Geerts
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2010
Materias:	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/dbfab43968d34192ba8f1f3adc8a528e
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spelling	oai:doaj.org-article:dbfab43968d34192ba8f1f3adc8a528e2021-12-02T06:29:36ZNot 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 synapse1176-63281178-2021https://doaj.org/article/dbfab43968d34192ba8f1f3adc8a528e2010-09-01T00:00:00Zhttp://www.dovepress.com/not-all-partial-dopamine-d2-receptor-agonists-are-the-same-in-treating-a5226https://doaj.org/toc/1176-6328https://doaj.org/toc/1178-2021Athan Spiros1, Robert Carr1, Hugo Geerts1,21In Silico Biosciences, Berwyn, PA, USA; 2School of Medicine, University of Pennsylvania, PA, USAAbstract: 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&ndash;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 Athan SpirosRobert CarrHugo GeertsDove Medical PressarticleNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENNeuropsychiatric Disease and Treatment, Vol 2010, Iss Issue 1, Pp 589-603 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
spellingShingle	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 Athan Spiros Robert Carr Hugo Geerts 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
description	Athan Spiros1, Robert Carr1, Hugo Geerts1,21In Silico Biosciences, Berwyn, PA, USA; 2School of Medicine, University of Pennsylvania, PA, USAAbstract: 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&ndash;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
format	article
author	Athan Spiros Robert Carr Hugo Geerts
author_facet	Athan Spiros Robert Carr Hugo Geerts
author_sort	Athan Spiros
title	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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	Dove Medical Press
publishDate	2010
url	https://doaj.org/article/dbfab43968d34192ba8f1f3adc8a528e
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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

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