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

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

SUBMITTER: O'Brien ES 

PROVIDER: S-EPMC11998091 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature