Discovery and Structural Explorations of G-Protein Biased μ-Opioid Receptor Agonists

Compounds that activate only the G-protein signalling pathway represent an effective strategy for making safer opioids. In the present study, we report the design, synthesis and evaluation of two classes of novel PZM21 derivatives containing the benzothiophene ring and biphenyl ring group respectively as biased mu-opioid receptor (mu OR) agonists. The new compound SWG-LX-33 showed potent mu OR agonist activity and produced mu OR-dependent analgesia. SWG-LX-33 does not activate the beta-arrestin-2 signalling pathway in vitro even at high concentrations. Computational docking demonstrated the amino acid residue ASN150 to be critical for the weak efficacy and potency of mu OR agonists in arrestin recruitment.

Automated summary

This study reports the design, synthesis, and evaluation of two classes of compounds as biased mu-opioid receptor agonists. Among them, SWG-LX-33 exhibits potent mu-opioid receptor agonist activity and analgesic effect, without activating the beta-arrestin signaling pathway.