Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors
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 und...
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| Format: | Article |
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Nature Publishing Group
2017
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| Online Access: | https://eprints.nottingham.ac.uk/50603/ |
| _version_ | 1848798293910355968 |
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| author | Sykes, David A. Moore, Holly Stott, Lisa Holliday, Nicholas Javitch, Jonathan A. Lane, J. Robert Charlton, Steven J. |
| author_facet | Sykes, David A. Moore, Holly Stott, Lisa Holliday, Nicholas Javitch, Jonathan A. Lane, J. Robert Charlton, Steven J. |
| author_sort | Sykes, David A. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:17:29Z |
| format | Article |
| id | nottingham-50603 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:17:29Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-506032020-05-04T19:10:35Z https://eprints.nottingham.ac.uk/50603/ 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. 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. Nature Publishing Group 2017-10-02 Article PeerReviewed Sykes, David A., Moore, Holly, Stott, Lisa, Holliday, Nicholas, Javitch, Jonathan A., Lane, J. Robert and Charlton, Steven J. (2017) Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors. Nature Communications, 8 (1). 763/1-763/11. ISSN 2041-1723 Neurotransmitters; Receptor pharmacology https://www.nature.com/articles/s41467-017-00716-z doi:10.1038/s41467-017-00716-z doi:10.1038/s41467-017-00716-z |
| spellingShingle | Neurotransmitters; Receptor pharmacology Sykes, David A. Moore, Holly Stott, Lisa Holliday, Nicholas Javitch, Jonathan A. Lane, J. Robert Charlton, Steven J. Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors |
| title | Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors |
| title_full | Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors |
| title_fullStr | Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors |
| title_full_unstemmed | Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors |
| title_short | Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors |
| title_sort | extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine d2 receptors |
| topic | Neurotransmitters; Receptor pharmacology |
| url | https://eprints.nottingham.ac.uk/50603/ https://eprints.nottingham.ac.uk/50603/ https://eprints.nottingham.ac.uk/50603/ |