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  3. A µ-opioid receptor modulator that works cooperatively with naloxone

A µ-opioid receptor modulator that works cooperatively with naloxone

  • Nature. 2024 Jul;631(8021):686-693. doi: 10.1038/s41586-024-07587-7.
Evan S O'Brien 1,  Vipin Ashok Rangari 2,  Amal El Daibani 2,  Shainnel O Eans 3,  Haylee R Hammond 3,  Elizabeth White 1,  Haoqing Wang 1,  Yuki Shiimura 1 4,  Kaavya Krishna Kumar 1,  Qianru Jiang 2,  Kevin Appourchaux 2,  Weijiao Huang 1,  Chensong Zhang 5,  Brandon J Kennedy 6,  Jesper M Mathiesen 7,  Tao Che 2,  Jay P McLaughlin 8,  Susruta Majumdar 9,  Brian K Kobilka 10
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
  • 2 Center for Clinical Pharmacology, University of Health Sciences and Pharmacy at St Louis and Washington University School of Medicine, St Louis, MO, USA.
  • 3 Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA.
  • 4 Division of Molecular Genetics, Institute of Life Science, Kurume University, Fukuoka, Japan.
  • 5 Division of CryoEM and Bioimaging, SSRL, SLAC National Acceleration Laboratory, Menlo Park, CA, USA.
  • 6 Lotus Separations, Princeton University, Princeton, NJ, USA.
  • 7 Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
  • 8 Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA. jpmclaughlin@ufl.edu.
  • 9 Center for Clinical Pharmacology, University of Health Sciences and Pharmacy at St Louis and Washington University School of Medicine, St Louis, MO, USA. susrutam@wustl.edu.
  • 10 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. kobilka@stanford.edu.
PMID: 38961287 DOI: 10.1038/s41586-024-07587-7
Abstract

The µ-opioid receptor (µOR) is a well-established target for analgesia1, yet conventional Opioid Receptor agonists cause serious adverse effects, notably addiction and respiratory depression. These factors have contributed to the current opioid overdose epidemic driven by fentanyl2, a highly potent synthetic opioid. µOR negative allosteric modulators (NAMs) may serve as useful tools in preventing opioid overdose deaths, but promising chemical scaffolds remain elusive. Here we screened a large DNA-encoded chemical library against inactive µOR, counter-screening with active, G-protein and agonist-bound receptor to 'steer' hits towards conformationally selective modulators. We discovered a NAM compound with high and selective enrichment to inactive µOR that enhances the affinity of the key opioid overdose reversal molecule, naloxone. The NAM works cooperatively with naloxone to potently block opioid agonist signalling. Using cryogenic electron microscopy, we demonstrate that the NAM accomplishes this effect by binding a site on the extracellular vestibule in direct contact with naloxone while stabilizing a distinct inactive conformation of the extracellular portions of the second and seventh transmembrane helices. The NAM alters orthosteric ligand kinetics in therapeutically desirable ways and works cooperatively with low doses of naloxone to effectively inhibit various morphine-induced and fentanyl-induced behavioural effects in vivo while minimizing withdrawal behaviours. Our results provide detailed structural insights into the mechanism of negative allosteric modulation of the µOR and demonstrate how this can be exploited in vivo.

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