IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v8y2017i1d10.1038_s41467-017-00716-z.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-017-00716-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-017-00716-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00716-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.