A μ-opioid receptor modulator that works cooperatively with naloxone

• 成果类型: Article
• 署名作者: O'Brien, Evan S.; Rangari, Vipin Ashok; El Daibani, Amal; Eans, Shainnel O.; Hammond, Haylee R.; White, Elizabeth; Wang, Haoqing; Shiimura, Yuki; Kumar, Kaavya Krishna; Jiang, Qianru; Appourchaux, Kevin; Huang, Weijiao; Zhang, Chensong; Kennedy, Brandon J.; Mathiesen, Jesper M.; Che, Tao; McLaughlin, Jay P.; Majumdar, Susruta; Kobilka, Brian K.
• 署名单位: Stanford University; University of Health Sciences & Pharmacy in St. Louis; Washington University (WUSTL); State University System of Florida; University of Florida; Kurume University; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; Princeton University; University of Copenhagen
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6153
• DOI: 10.1038/s41586-024-07587-7
• 发表日期: 2024-07-18
• 关键词: gui membrane-builder; molecular-dynamics; software news; antagonism; agonism; antinociception; efficacy; morphine; SYSTEM; motion

摘要

The mu -opioid receptor (mu OR) 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. mu OR 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 mu OR, 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 mu OR 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 mu OR and demonstrate how this can be exploited in vivo. A newly discovered negative allosteric modulator of the mu -opioid receptor works together with naloxone to potently block opioid agonist signalling with reduced adverse effects.