Discovery of Biased Mu‐Opioid Receptor Agonists for the Treatment of Pain

Abstract G protein‐biased mu‐opioid receptor (MOR) agonists have been developed as promising new potent analgesic drugs with fewer adverse side effects than standard MOR agonists. PZM21 represents a unique chemotype unrelated to known opioids, which makes it a desirable lead for modification to find analgesics with new chemical entities. In the present study, we synthesized and tested novel PZM21 derivatives as potent biased MOR agonists by introducing a benzodioxolane group to replace the hydroxybenzene of PZM21. The new compounds displayed more potent analgesic activities in vivo and greater bias toward G protein signaling in vitro than did PZM21. These results suggest that the benzodioxolane group is essential for the maintenance of bias. Compounds 7 i (( S )‐1‐(3‐(benzo[ d ][1,3]dioxol‐4‐yl)‐2‐(dimethylamino)propyl)‐3‐phenethylurea) and 7 j (( S )‐1‐(3‐(benzo[ d ][1,3]dioxol‐4‐yl)‐2‐(dimethylamino)propyl)‐3‐benzylurea) could serve as new leads for further modifications to find novel biased MOR agonists with greater G protein signaling potency and less β‐arrestin‐2 recruitment.