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Discovery of Biased Mu‐Opioid Receptor Agonists for the Treatment of Pain
Author(s) -
Ma Mengjun,
Li Xiang,
Tong Kun,
Cheng Jingchao,
Yu Zixing,
Ren Fengxia,
Zhong Bohua,
Shi Weiguo
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900575
Subject(s) - analgesic , chemistry , pharmacology , opioid , agonist , functional selectivity , receptor , potency , in vivo , μ opioid receptor , partial agonist , adverse effect , stereochemistry , in vitro , medicine , biology , biochemistry , microbiology and biotechnology
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.