Structure-Based Evolution of G Protein-Biased μ-Opioid Receptor Agonists.

ABSTRACT: The μ-opioid receptor (μOR) is the major target for opioid analgesics. Activation of μOR initiates signaling through G protein pathways as well as through β-arrestin recruitment. μOR agonists that are biased towards G protein signaling pathways demonstrate diminished side effects. PZM21, discovered by computational docking, is a G protein biased μOR agonist. Here we report the cryoEM structure of PZM21 bound μOR in complex with G_i protein. Structure-based evolution led to multiple PZM21 analogs with more pronounced G_i protein bias and increased lipophilicity to improve CNS penetration. Among them, FH210 shows extremely low potency and efficacy for arrestin recruitment. We further determined the cryoEM structure of FH210 bound to μOR in complex with G_i prote

SUBMITTER: Wang H 

PROVIDER: S-EPMC9322534 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature