ArticleNeuropsychiatric disease and treatment2010
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.
Article in Neuropsychiatric disease and treatment, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 40 citations in OpenAlex.
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- Mechanistic modeling as an explanatory tool for clinical treatment of chronic catatonia.Frontiers in pharmacology · 2022Article
- Toward Predicting Impact of Common Genetic Variants on Schizophrenia Clinical Responses With Antipsychotics: A Quantitative System Pharmacology Study.Frontiers in neuroscience · 2021Article
- Learning from amyloid trials in Alzheimer's disease. A virtual patient analysis using a quantitative systems pharmacology approach.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2020Article
- A modeling informed quantitative approach to salvage clinical trials interrupted due to COVID-19.Alzheimer's & dementia (New York, N. Y.) · 2020Article
- Neuronal Circuit-Based Computer Modeling as a Phenotypic Strategy for CNS R&D.Frontiers in neuroscience · 2019Article
- Predicting parkinsonism side-effects of antipsychotic polypharmacy prescribed in secondary mental healthcare.Journal of psychopharmacology (Oxford, England) · 2018Article
- Impact of amyloid-beta changes on cognitive outcomes in Alzheimer's disease: analysis of clinical trials using a quantitative systems pharmacology model.Alzheimer's research & therapy · 2018Article
- Genetic variants in Alzheimer disease - molecular and brain network approaches.Nature reviews. Neurology · 2016Review
- A Humanized Clinically Calibrated Quantitative Systems Pharmacology Model for Hypokinetic Motor Symptoms in Parkinson's Disease.Frontiers in pharmacology · 2016Article
- Assessing the synergy between cholinomimetics and memantine as augmentation therapy in cognitive impairment in schizophrenia. A virtual human patient trial using quantitative systems pharmacology.Frontiers in pharmacology · 2015Article
- Prediction of Efficacy of Vabicaserin, a 5-HT2C Agonist, for the Treatment of Schizophrenia Using a Quantitative Systems Pharmacology Model.CPT: pharmacometrics & systems pharmacology · 2014Article
- A computer-based quantitative systems pharmacology model of negative symptoms in schizophrenia: exploring glycine modulation of excitation-inhibition balance.Frontiers in pharmacology · 2014Article
- Quantitative systems pharmacology as an extension of PK/PD modeling in CNS research and development.Journal of pharmacokinetics and pharmacodynamics · 2013Article
- A quantitative system pharmacology computer model for cognitive deficits in schizophrenia.CPT: pharmacometrics & systems pharmacology · 2013Article
- A strategy for developing new treatment paradigms for neuropsychiatric and neurocognitive symptoms in Alzheimer's disease.Frontiers in pharmacology · 2013Article
- Has the time come for predictive computer modeling in CNS drug discovery and development?CPT: pharmacometrics & systems pharmacology · 2012Article
- A quantitative way to estimate clinical off-target effects for human membrane brain targets in CNS research and development.Journal of experimental pharmacology · 2012Article
- Simulations of symptomatic treatments for Alzheimer's disease: computational analysis of pathology and mechanisms of drug action.Alzheimer's research & therapy · 2012Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.