期刊
ACS CHEMICAL NEUROSCIENCE
卷 11, 期 12, 页码 1781-1790出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.0c00191
关键词
Structure-activity relationship; MOR agonist; salvinorin A; antinociceptive activity; biased ligand; functional selectivity
资金
- Health Research Council of New Zealand
- NSF [0320648]
- AFPE Predoctoral Fellowship in Pharmaceutical Sciences
- NIH [S10RR024664]
- [DA018151]
- [GM001385]
- [GM008545]
Previous structure-activity relationship (SAR) studies identified the first centrally acting, non-nitrogenous mu-opioid receptor (MOR) agonist, kurkinorin (1), derived from salvinorin A. In an effort to further probe the physiological effects induced upon activation of MORs with this nonmorphine scaffold, a variety of analogues were synthesized and evaluated in vitro for their ability to activate G-proteins and recruit beta-arrestin-2 upon MOR activation. Through these studies, compounds that are potent agonists at MORs and either biased toward beta-arrestin-2 recruitment or biased toward G-protein activation have been identified. One such compound, 25, has potent activity and selectivity at the MOR over KOR with bias for G-protein activation. Impressively, 25 is over 100x more potent than morphine and over 5x more potent than fentanyl in vitro and elicits antinociception with limited tolerance development in vivo. This is especially significant given that 25 lacks a basic nitrogen and other ionizable groups present in other opioid ligand classes.
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