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

Author

Listed:
  • David A. Sykes

    (University of Nottingham)

  • Holly Moore

    (Columbia University
    New York State Psychiatric Institute)

  • Lisa Stott

    (University of Nottingham)

  • Nicholas Holliday

    (University of Nottingham)

  • Jonathan A. Javitch

    (Columbia University
    Columbia University
    New York State Psychiatric Institute)

  • J. Robert Lane

    (Monash University)

  • Steven J. Charlton

    (University of Nottingham)

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.

Suggested Citation

  • David A. Sykes & Holly Moore & Lisa Stott & Nicholas Holliday & Jonathan A. Javitch & J. Robert Lane & Steven J. Charlton, 2017. "Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00716-z
    DOI: 10.1038/s41467-017-00716-z
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    Cited by:

    1. Fabrizio Clarelli & Adam Palmer & Bhupender Singh & Merete Storflor & Silje Lauksund & Ted Cohen & Sören Abel & Pia Abel zur Wiesch, 2020. "Drug-target binding quantitatively predicts optimal antibiotic dose levels in quinolones," PLOS Computational Biology, Public Library of Science, vol. 16(8), pages 1-27, August.
    2. Yuya Maruyama & Yusuke Ohsawa & Takayuki Suzuki & Yuko Yamauchi & Kohsuke Ohno & Hitoshi Inoue & Akitoshi Yamamoto & Morimichi Hayashi & Yuji Okuhara & Wataru Muramatsu & Kano Namiki & Naho Hagiwara &, 2024. "Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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