Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors
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Abstract Atypical antipsychotic drugs (APDs) have been hypothesized to show reduced extrapyramidal side effects (EPS) due to their rapid dissociation from the dopamine D 2 receptor. However, support for this hypothesis is limited to a relatively small number of observations made across several decades and under different experimental conditions. Here we show that association rates, but not dissociation rates, correlate with EPS. We measured the kinetic binding properties of a series of typical and atypical APDs in a novel time-resolved fluorescence resonance energy transfer assay, and correlated these properties with their EPS and prolactin-elevating liabilities at therapeutic doses. EPS are robustly predicted by a rebinding model that considers the microenvironment of postsynaptic D 2 receptors and integrates association and dissociation rates to calculate the net rate of reversal of receptor blockade. Thus, optimizing binding kinetics at the D 2 receptor may result in APDs with improved therapeutic profile.
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Medical and nursing practitioners who themselves engage in healthy lifestyle behaviours are more likely to recommend and endorse such behaviours for patients.
“This approach builds on existing evidence that medical and nursing practitioners who engage in healthy lifestyle behaviours themselves are more likely to recommend and endorse such behaviours for patients.250”
From The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness (2019) · cites this paper as [250]
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References 71 · Cited by 218
Research works printed but not linked: 2
- [10]Meltzer HY Matsubara S Lee JC Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values J. Pharmacol. Exp. Ther. 1989 251 238 246 2571717
- [69]Stone T. W. CNS Neurotransmitters and Neuromodulators: Dopamine (CRC Press, 1996).
- Authors
- Sykes, D. A., Moore, H., Stott, L., Holliday, N., Javitch, J. A., Lane, J. R., & Charlton, S. J.
- Affiliations
- University of Nottingham (GB)
- New York State Psychiatric Institute (US)
- Monash University (AU)
- Corresponding author
- Charlton, Steven J.
- ORCID
- Venue
- Nature Communications
- Published
- 2017-10-02
- Volume
- 8
- Issue
- 1
- Pages
- 763-763
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5624946
- OpenAlex
- W2760367307
- Cited by
- 218
- References
- 71
- Citations by year
- 2026: 13 · 2025: 34 · 2024: 18 · 2023: 32 · 2022: 27 · 2021: 22 · 2020: 22 · 2019: 27 · 2018: 21 · 2012: 1
- FWCI
- 7.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Nottingham ePrints (University of Nottingham) (submittedVersion, cc-by)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Funders
- New York State Office of Mental Health
- National Institutes of Health (DA022413)
- Biotechnology and Biological Sciences Research Council (1233632)
- National Institute of Mental Health (P50MH086404, R01MH054137)
- National Institute on Drug Abuse (K05DA022413)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- extrapyramidal symptoms, atypical antipsychotics, dopamine D2 receptor, receptor binding kinetics, association rate, dissociation rate, prolactin elevation, typical antipsychotics, time-resolved fluorescence resonance energy transfer
- MeSH terms
- Animals, Basal Ganglia Diseases, Cricetulus, Humans, Hyperprolactinemia, Antipsychotic Agents, CHO Cells, Receptors, Dopamine D2, Dopamine Antagonists, Fluorescence Resonance Energy Transfer
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