TY - JOUR
T1 - Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum
T2 - Design, Synthesis, and Evaluation of Analogues with Improved Potency and G-protein Activation Bias at the μ-Opioid Receptor
AU - Crowley, Rachel S.
AU - Riley, Andrew P.
AU - Alder, Amy F.
AU - Anderson, Richard J.
AU - Luo, Dan
AU - Kaska, Sophia
AU - Maynez, Pamela
AU - Kivell, Bronwyn M.
AU - Prisinzano, Thomas E.
N1 - Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/6/17
Y1 - 2020/6/17
N2 - Previous structure-activity relationship (SAR) studies identified the first centrally acting, non-nitrogenous μ-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 β-arrestin-2 upon MOR activation. Through these studies, compounds that are potent agonists at MORs and either biased toward β-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 100× more potent than morphine and over 5× 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.
AB - Previous structure-activity relationship (SAR) studies identified the first centrally acting, non-nitrogenous μ-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 β-arrestin-2 upon MOR activation. Through these studies, compounds that are potent agonists at MORs and either biased toward β-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 100× more potent than morphine and over 5× 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.
KW - MOR agonist
KW - Structure-activity relationship
KW - antinociceptive activity
KW - biased ligand
KW - functional selectivity
KW - salvinorin A
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U2 - 10.1021/acschemneuro.0c00191
DO - 10.1021/acschemneuro.0c00191
M3 - Article
C2 - 32383854
AN - SCOPUS:85085878440
VL - 11
SP - 1781
EP - 1790
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 12
ER -