Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site
- Memorial Sloan Kettering Cancer Center, United States
- University of North Carolina, United States
- The Bridge Institute, University of Southern California, United States
- Columbia University, United States
- St. Louis College of Pharmacy and Washington University School of Medicine, United States
- Washington University in St. Louis, United States
- Washington University, United States
- University of Florida, United States
- University of Southern California, United States
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
Abdelfattah Faouzi
Jonathan A Javitch
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.
Reviewing Editor
- Olga Boudker, Weill Cornell Medicine, United States
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.
Version history
- Received: March 1, 2020
- Accepted: February 7, 2021
- Accepted Manuscript published: February 8, 2021 (version 1)
- 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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Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site
eLife 10:e56519.
https://doi.org/10.7554/eLife.56519
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