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

Abstract 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 μ‐opioid receptor (μOR) agonists. The new compound SWG‐LX‐33 showed potent μOR agonist activity and produced μOR‐dependent analgesia. SWG‐LX‐33 does not activate the β‐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 μOR agonists in arrestin recruitment.