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Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors

Sykes, David A.; Moore, Holly; Stott, Lisa; Holliday, Nicholas; Javitch, Jonathan A.; Lane, J. Robert; Charlton, Steven J.

Authors

David A. Sykes

Holly Moore

Lisa Stott

Jonathan A. Javitch

ROB LANE ROB.LANE@NOTTINGHAM.AC.UK
Associate Professor

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STEVEN CHARLTON Steven.Charlton@nottingham.ac.uk
Professor of Molecular Pharmacology and Drug Discovery



Abstract

Atypical antipsychotic drugs (APDs) have been hypothesized to show reduced extrapyramidal side effects (EPS) due to their rapid dissociation from the dopamine D2 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 D2 receptors and integrates association and dissociation rates to calculate the net rate of reversal of receptor blockade. Thus, optimizing binding kinetics at the D2 receptor may result in APDs with improved therapeutic profile.

Citation

Sykes, D. A., Moore, H., Stott, L., Holliday, N., Javitch, J. A., Lane, J. R., & Charlton, S. J. (2017). Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors. Nature Communications, 8(1), Article 763. https://doi.org/10.1038/s41467-017-00716-z

Journal Article Type Article
Acceptance Date Jul 20, 2017
Online Publication Date Oct 2, 2017
Publication Date 2017-12
Deposit Date Mar 22, 2018
Publicly Available Date Mar 29, 2024
Journal Nature Communications
Electronic ISSN 2041-1723
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 8
Issue 1
Article Number 763
DOI https://doi.org/10.1038/s41467-017-00716-z
Keywords Neurotransmitters; Receptor pharmacology
Public URL https://nottingham-repository.worktribe.com/output/886219
Publisher URL https://www.nature.com/articles/s41467-017-00716-z

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