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Publication Abstract from PubMed

The mu-opioid receptor (muOR) is the major target for opioid analgesics. Activation of muOR initiates signaling through G protein pathways as well as through beta-arrestin recruitment. muOR agonists that are biased towards G protein signaling pathways demonstrate diminished side effects. PZM21, discovered by computational docking, is a G protein biased muOR agonist. Here we report the cryoEM structure of PZM21 bound muOR 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 muOR in complex with G(i) protein and confirmed its expected binding pose. The structural and pharmacological studies reveal a potential mechanism to reduce beta-arrestin recruitment by the muOR, and hold promise for developing next-generation analgesics with fewer adverse effects.

Structure-Based Evolution of G Protein-Biased mu-Opioid Receptor Agonists.,Wang H, Hetzer F, Huang W, Qu Q, Meyerowitz J, Kaindl J, Hubner H, Skiniotis G, Kobilka BK, Gmeiner P Angew Chem Int Ed Engl. 2022 Jun 27;61(26):e202200269. doi: , 10.1002/anie.202200269. Epub 2022 Apr 29. PMID:35385593^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.