ArticleJournal of experimental pharmacology2012
A quantitative way to estimate clinical off-target effects for human membrane brain targets in CNS research and development.
Article in Journal of experimental pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
15 citing papers in PubMed, 24 citations in OpenAlex.
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- A quantitative systems pharmacology model for simulating OFF-Time in augmentation trials for Parkinson's disease: application to preladenant.Journal of pharmacokinetics and pharmacodynamics · 2022Article
- Computational Approaches for Supporting Combination Therapy in the Post-Aducanumab Era in Alzheimer's Disease.Journal of Alzheimer's disease reports · 2021Review
- 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
- Quantitative Systems Pharmacology for Neuroscience Drug Discovery and Development: Current Status, Opportunities, and Challenges.CPT: pharmacometrics & systems pharmacology · 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
- 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
- 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
- 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
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
2 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although many preclinical programs in central nervous system research and development intend to develop highly selective and potent molecules directed at the primary target, they often act upon other off-target receptors. The simple rule of taking the ratios of affinities for the candidate drug at the different receptors is flawed since the affinity of the endogenous ligand for that off-target receptor or drug exposure is not taken into account. We have developed a mathematical receptor competition model that takes into account the competition between active drug moiety and the endogenous neurotransmitter to better assess the off-target effects on postsynaptic receptor activation under the correct target exposure conditions. As an example, we investigate the possible functional effects of the weak off-target effects for dopamine-1 receptor (D1R) in a computer simulation of a dopaminergic cortical synapse that is calibrated using published fast-cyclic rodent voltammetry and human imaging data in subjects with different catechol-O-methyltransferase genotypes. We identify the conditions under which off-target effects at the D1R can lead to clinically detectable consequences on cognitive tests, such as the N-back working memory test. We also demonstrate that certain concentrations of dimebolin (Dimebon), a recently tested Alzheimer drug, can affect D1R activation resulting in clinically detectable cognitive decrease. This approach can be extended to other receptor systems and can improve the selection of clinical candidate compounds by potentially dialing-out harmful off-target effects or dialing-in beneficial off-target effects in a quantitative and controlled way.
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What OpenQuestion holds
Registered trials
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.