Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity

  1. Sina B Kirchhofer
  2. Victor Jun Yu Lim
  3. Sebastian Ernst
  4. Noemi Karsai
  5. Ruland G Julia
  6. Meritxell Canals
  7. Peter Kolb  Is a corresponding author
  8. Moritz Bünemann  Is a corresponding author
  1. Philipp University of Marburg, Germany
  2. University of Nottingham, United Kingdom

Abstract

The µ opioid receptor (MOR) is the key target for analgesia, but the application of opioids is accompanied by several issues. There is a wide range of opioid analgesics, differing in their chemical structure and their properties of receptor activation and subsequent effects. A better understanding of ligand-receptor interactions and the resulting effects is important. Here, we calculated the respective binding poses for several opioids and analyzed interaction fingerprints between ligand and receptor. We further corroborated the interactions experimentally by cellular assays. As MOR was observed to display ligand-induced modulation of activity due to changes in membrane potential, we further analyzed the effects of voltage sensitivity on this receptor. Combining in silico and in vitro approaches, we defined discriminating interaction patterns responsible for ligand-specific voltage sensitivity and present new insights into their specific effects on activation of the MOR.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1, 3, 4, 5, 6.

Article and author information

Author details

  1. Sina B Kirchhofer

    Department of Pharmacology and Clinical Pharmacy, Philipp University of Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6285-9054
  2. Victor Jun Yu Lim

    Department of Pharmaceutical Chemistry, Philipp University of Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Sebastian Ernst

    Department of Pharmacology and Clinical Pharmacy, Philipp University of Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Noemi Karsai

    Division of Physiology, Pharmacology and Neuroscience, University of Nottingham, Nottingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0009-0000-3948-4071
  5. Ruland G Julia

    Department of Pharmacology and Clinical Pharmacy, Philipp University of Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Meritxell Canals

    Division of Physiology, Pharmacology and Neuroscience, University of Nottingham, Nottingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Peter Kolb

    Department of Pharmaceutical Chemistry, Philipp University of Marburg, Marburg, Germany
    For correspondence
    peter.kolb@uni-marburg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4089-614X
  8. Moritz Bünemann

    Department of Pharmacology and Clinical Pharmacy, Philipp University of Marburg, Marburg, Germany
    For correspondence
    Moritz.buenemann@staff.uni-marburg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2259-4378

Funding

European Commission (H2020-MSCA- 860229)

  • Meritxell Canals

United Kingdom Academy of Medical Siences Proffessorship

  • Meritxell Canals

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Kenton J Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States

Version history

  1. Preprint posted: December 3, 2021 (view preprint)
  2. Received: July 25, 2023
  3. Accepted: November 19, 2023
  4. Accepted Manuscript published: November 20, 2023 (version 1)
  5. Version of Record published: February 7, 2024 (version 2)

Copyright

© 2023, Kirchhofer et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sina B Kirchhofer
  2. Victor Jun Yu Lim
  3. Sebastian Ernst
  4. Noemi Karsai
  5. Ruland G Julia
  6. Meritxell Canals
  7. Peter Kolb
  8. Moritz Bünemann
(2023)
Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity
eLife 12:e91291.
https://doi.org/10.7554/eLife.91291

Share this article

https://doi.org/10.7554/eLife.91291

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