Papers of the Week

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 MOR agonists. New compounds 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 is critical for the weak efficacy and potency of MOR agonist in arrestin recruitment.