A µ-opioid receptor modulator that works cooperatively with naloxone

Evan S. O’Brien, Vipin Ashok Rangari, Amal El Daibani, Shainnel O. Eans, Haylee R. Hammond, Elizabeth White, Haoqing Wang, Yuki Shiimura, Kaavya Krishna Kumar, Qianru Jiang, Kevin Appourchaux, Weijiao Huang, Chensong Zhang, Brandon J. Kennedy, Jesper M. Mathiesen, Tao Che, Jay P. McLaughlin (), Susruta Majumdar () and Brian K. Kobilka ()
Additional contact information
Evan S. O’Brien: Stanford University School of Medicine
Vipin Ashok Rangari: University of Health Sciences and Pharmacy at St Louis and Washington University School of Medicine
Amal El Daibani: University of Health Sciences and Pharmacy at St Louis and Washington University School of Medicine
Shainnel O. Eans: University of Florida
Haylee R. Hammond: University of Florida
Elizabeth White: Stanford University School of Medicine
Haoqing Wang: Stanford University School of Medicine
Yuki Shiimura: Stanford University School of Medicine
Kaavya Krishna Kumar: Stanford University School of Medicine
Qianru Jiang: University of Health Sciences and Pharmacy at St Louis and Washington University School of Medicine
Kevin Appourchaux: University of Health Sciences and Pharmacy at St Louis and Washington University School of Medicine
Weijiao Huang: Stanford University School of Medicine
Chensong Zhang: SLAC National Acceleration Laboratory
Brandon J. Kennedy: Princeton University
Jesper M. Mathiesen: University of Copenhagen
Tao Che: University of Health Sciences and Pharmacy at St Louis and Washington University School of Medicine
Jay P. McLaughlin: University of Florida
Susruta Majumdar: University of Health Sciences and Pharmacy at St Louis and Washington University School of Medicine
Brian K. Kobilka: Stanford University School of Medicine

Nature, 2024, vol. 631, issue 8021, 686-693

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07587-7

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