Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Design, Synthesis, and Evaluation of Analogues with Improved Potency and G-protein Activation Bias at the μ-Opioid Receptor

Rachel S. Crowley; Andrew P. Riley; Amy F. Alder; Richard J. Anderson; Dan Luo; Sophia Kaska; Pamela Maynez; Bronwyn M. Kivell; Thomas E. Prisinzano

doi:10.1021/acschemneuro.0c00191

Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Design, Synthesis, and Evaluation of Analogues with Improved Potency and G-protein Activation Bias at the μ-Opioid Receptor

Rachel S. Crowley, Andrew P. Riley, Amy F. Alder, Richard J. Anderson, Dan Luo, Sophia Kaska, Pamela Maynez, Bronwyn M. Kivell, Thomas E. Prisinzano

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1781-1790
Number of pages	10
Journal	ACS Chemical Neuroscience
Volume	11
Issue number	12
DOIs	https://doi.org/10.1021/acschemneuro.0c00191
State	Published - Jun 17 2020

Bibliographical note

Funding Information:
This work was supported by DA018151 and GM001385 (to T.E.P.), GM008545 (to A.P.R. and R.S.C.), AFPE Predoctoral Fellowship in Pharmaceutical Sciences (to R.S.C.), and the Health Research Council of New Zealand (to B.M.K.). Support for the NMR instrumentation was provided by NIH Shared Instrumentation Grant No. S10RR024664 and NSF Major Research Instrumentation Grant No. 0320648. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse, National Institutes of Health, or the National Science Foundation.

Funding Information:
This work was supported by DA018151 and GM001385 (to T.E.P.), GM008545 (to A.P.R. and R.S.C.), AFPE Predoctoral Fellowship in Pharmaceutical Sciences (to R.S.C.), and the Health Research Council of New Zealand (to B.M.K.). Support for the NMR instrumentation was provided by NIH Shared Instrumentation Grant No. S10RR024664 and NSF Major Research Instrumentation Grant No. 0320648. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse, National Institutes of Health or the National Science Foundation.

Publisher Copyright:
© 2020 American Chemical Society.

Keywords

MOR agonist
Structure-activity relationship
antinociceptive activity
biased ligand
functional selectivity
salvinorin A

ASJC Scopus subject areas

Biochemistry
Physiology
Cognitive Neuroscience
Cell Biology

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10.1021/acschemneuro.0c00191

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Crowley, R. S., Riley, A. P., Alder, A. F., Anderson, R. J., Luo, D., Kaska, S., Maynez, P., Kivell, B. M., & Prisinzano, T. E. (2020). Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Design, Synthesis, and Evaluation of Analogues with Improved Potency and G-protein Activation Bias at the μ-Opioid Receptor. ACS Chemical Neuroscience, 11(12), 1781-1790. https://doi.org/10.1021/acschemneuro.0c00191

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title = "Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Design, Synthesis, and Evaluation of Analogues with Improved Potency and G-protein Activation Bias at the μ-Opioid Receptor",

abstract = "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.",

keywords = "MOR agonist, Structure-activity relationship, antinociceptive activity, biased ligand, functional selectivity, salvinorin A",

author = "Crowley, {Rachel S.} and Riley, {Andrew P.} and Alder, {Amy F.} and Anderson, {Richard J.} and Dan Luo and Sophia Kaska and Pamela Maynez and Kivell, {Bronwyn M.} and Prisinzano, {Thomas E.}",

note = "Funding Information: This work was supported by DA018151 and GM001385 (to T.E.P.), GM008545 (to A.P.R. and R.S.C.), AFPE Predoctoral Fellowship in Pharmaceutical Sciences (to R.S.C.), and the Health Research Council of New Zealand (to B.M.K.). Support for the NMR instrumentation was provided by NIH Shared Instrumentation Grant No. S10RR024664 and NSF Major Research Instrumentation Grant No. 0320648. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse, National Institutes of Health, or the National Science Foundation. Funding Information: This work was supported by DA018151 and GM001385 (to T.E.P.), GM008545 (to A.P.R. and R.S.C.), AFPE Predoctoral Fellowship in Pharmaceutical Sciences (to R.S.C.), and the Health Research Council of New Zealand (to B.M.K.). Support for the NMR instrumentation was provided by NIH Shared Instrumentation Grant No. S10RR024664 and NSF Major Research Instrumentation Grant No. 0320648. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse, National Institutes of Health or the National Science Foundation. Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",

year = "2020",

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language = "English",

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Crowley, RS, Riley, AP, Alder, AF, Anderson, RJ, Luo, D, Kaska, S, Maynez, P, Kivell, BM & Prisinzano, TE 2020, 'Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Design, Synthesis, and Evaluation of Analogues with Improved Potency and G-protein Activation Bias at the μ-Opioid Receptor', ACS Chemical Neuroscience, vol. 11, no. 12, pp. 1781-1790. https://doi.org/10.1021/acschemneuro.0c00191

Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Design, Synthesis, and Evaluation of Analogues with Improved Potency and G-protein Activation Bias at the μ-Opioid Receptor. / Crowley, Rachel S.; Riley, Andrew P.; Alder, Amy F. et al.
In: ACS Chemical Neuroscience, Vol. 11, No. 12, 17.06.2020, p. 1781-1790.

Research output: Contribution to journal › Article › peer-review

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AU - Luo, Dan

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N1 - Funding Information: This work was supported by DA018151 and GM001385 (to T.E.P.), GM008545 (to A.P.R. and R.S.C.), AFPE Predoctoral Fellowship in Pharmaceutical Sciences (to R.S.C.), and the Health Research Council of New Zealand (to B.M.K.). Support for the NMR instrumentation was provided by NIH Shared Instrumentation Grant No. S10RR024664 and NSF Major Research Instrumentation Grant No. 0320648. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse, National Institutes of Health, or the National Science Foundation. Funding Information: This work was supported by DA018151 and GM001385 (to T.E.P.), GM008545 (to A.P.R. and R.S.C.), AFPE Predoctoral Fellowship in Pharmaceutical Sciences (to R.S.C.), and the Health Research Council of New Zealand (to B.M.K.). Support for the NMR instrumentation was provided by NIH Shared Instrumentation Grant No. S10RR024664 and NSF Major Research Instrumentation Grant No. 0320648. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse, National Institutes of Health or the National Science Foundation. 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.

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Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Design, Synthesis, and Evaluation of Analogues with Improved Potency and G-protein Activation Bias at the μ-Opioid Receptor

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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