1. Biochemistry and Chemical Biology
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Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site

  1. Rajendra Uprety
  2. Tao Che
  3. Saheem A Zaidi
  4. Steven G Grinnell
  5. Balázs R Varga
  6. Abdelfattah Faouzi
  7. Samuel T Slocum
  8. Abdullah Allaoa
  9. András Varadi
  10. Melissa Nelson
  11. Sarah M Bernhard
  12. Elizaveta Kulko
  13. Valerie LeRouzic
  14. Shainnel O Eans
  15. Chloe A Simons
  16. Amanda Hunkele
  17. Joan Subrath
  18. Ying Xian Pan
  19. Jonathan A Javitch
  20. Jay P McLaughlin
  21. Bryan L Roth  Is a corresponding author
  22. Gavril W Pasternak
  23. Vsevolod Katritch  Is a corresponding author
  24. Susruta Majumdar  Is a corresponding author
  1. Memorial Sloan Kettering Cancer Center, United States
  2. University of North Carolina, United States
  3. The Bridge Institute, University of Southern California, United States
  4. Columbia University, United States
  5. St. Louis College of Pharmacy and Washington University School of Medicine, United States
  6. Washington University in St. Louis, United States
  7. Washington University, United States
  8. University of Florida, United States
  9. University of Southern California, United States
Research Article
  • Cited 7
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Cite this article as: eLife 2021;10:e56519 doi: 10.7554/eLife.56519

Abstract

Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with MP1104, to rationally design novel mixed mu (MOR) and kappa (KOR) opioid receptor agonists with reduced arrestin signaling. Analysis of structure-activity relationships for new MP1104 analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) as key for modulation of arrestin recruitment to both MOR and KOR. The lead compounds, MP1207 and MP1208, displayed MOR/KOR Gi-partial agonism with diminished arrestin signaling, showed efficient analgesia with attenuated liabilities, including respiratory depression and conditioned place preference and aversion in mice. The findings validate a novel structure-inspired paradigm for achieving beneficial in vivo profiles for analgesia through different mechanisms that include bias, partial agonism, and dual MOR/KOR agonism.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Rajendra Uprety

    Neurology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    Rajendra Uprety, RU have filed a provisional patent on MP1207 and related molecules..
  2. Tao Che

    Pharmacology, University of North Carolina, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  3. Saheem A Zaidi

    Department of Biological Sciences, Molecular & Computational Biology, The Bridge Institute, University of Southern California, Los Angeles, United States
    Competing interests
    Saheem A Zaidi, SZ has filed a provisional patent on MP1207 and related molecules..
  4. Steven G Grinnell

    Molecular Therapeutics, Columbia University, New York, United States
    Competing interests
    No competing interests declared.
  5. Balázs R Varga

    Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St Louis, United States
    Competing interests
    No competing interests declared.
  6. Abdelfattah Faouzi

    Clinical Pharmacology, Washington University in St. Louis, St Louis, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9059-4791
  7. Samuel T Slocum

    Pharmacology, University of North Carolina, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  8. Abdullah Allaoa

    Neurology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  9. András Varadi

    Neurology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5591-377X
  10. Melissa Nelson

    Molecular Therapeutics, Columbia University, New York, United States
    Competing interests
    No competing interests declared.
  11. Sarah M Bernhard

    Center for Clinical Pharmacology, Washington University, St Louis, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8549-0413
  12. Elizaveta Kulko

    Molecular Therapeutics, Columbia University, New York, United States
    Competing interests
    No competing interests declared.
  13. Valerie LeRouzic

    Neurology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  14. Shainnel O Eans

    Pharmacodyanamics, University of Florida, Gainesville, United States
    Competing interests
    No competing interests declared.
  15. Chloe A Simons

    Pharmacodyanamics, University of Florida, Gainesville, United States
    Competing interests
    No competing interests declared.
  16. Amanda Hunkele

    Neurology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  17. Joan Subrath

    Neurology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  18. Ying Xian Pan

    Neurology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    Ying Xian Pan, YXPis a co-founder of Sparian biosciences..
  19. Jonathan A Javitch

    Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7395-2967
  20. Jay P McLaughlin

    Pharmacodyanamics, University of Florida, Gainesville, United States
    Competing interests
    Jay P McLaughlin, JM has filed a provisional patent on MP1207 and related molecules..
  21. Bryan L Roth

    Department of Pharmacology, University of North Carolina, Chapel Hill, United States
    For correspondence
    bryan_roth@med.unc.edu
    Competing interests
    Bryan L Roth, BLR has filed a provisional patent on MP1207 and related molecules..
  22. Gavril W Pasternak

    Neurology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    Gavril W Pasternak, GWP is a co-founder of Sparian biosciences. GWP have filed a provisional patent on MP1207 and related molecules..
  23. Vsevolod Katritch

    Department of Biological Sciences, University of Southern California, Los Angeles, United States
    For correspondence
    katritch@usc.edu
    Competing interests
    Vsevolod Katritch, VK has filed a provisional patent on MP1207 and related molecules..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3883-4505
  24. Susruta Majumdar

    Center for Clinical Pharmacology, Washington University, st louis, United States
    For correspondence
    susrutam@email.wustl.edu
    Competing interests
    Susruta Majumdar, SM, is a co-founder of Sparian biosciences. SM have filed a provisional patent on MP1207 and related molecules..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2931-3823

Funding

National Institute on Drug Abuse (DA045884)

  • Susruta Majumdar

National Institute on Drug Abuse (DA045657)

  • Jonathan A Javitch

National Institute on Drug Abuse (DA046487)

  • Susruta Majumdar

National Institute on Alcohol Abuse and Alcoholism (AA026949)

  • Susruta Majumdar

National Institute on Drug Abuse (DA038858)

  • Vsevolod Katritch

National Institute on Drug Abuse (DA035764)

  • Bryan L Roth
  • Vsevolod Katritch

National Institute on Drug Abuse (DA007242,DA006241)

  • Ying Xian Pan
  • Gavril W Pasternak

National Institute on Drug Abuse (DA042888,DA046714)

  • Ying Xian Pan

National Institute of Mental Health (MH018870)

  • Steven G Grinnell

National Institute of Mental Health (MH112205)

  • Jonathan A Javitch

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

Ethics

Animal experimentation: All animal studies were preapproved by the Institutional Animal Care and Use Committees of University of Florida in accordance with the 2002 National Institutes of Health Guide for the Care and Use of Laboratory Animals. protocols 201808990 and 202011105.

Reviewing Editor

  1. Olga Boudker, Weill Cornell Medicine, United States

Publication history

  1. Received: March 1, 2020
  2. Accepted: February 7, 2021
  3. Accepted Manuscript published: February 8, 2021 (version 1)
  4. Version of Record published: February 26, 2021 (version 2)

Copyright

© 2021, Uprety 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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