Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability

Rachel Saylor Crowley; Andrew P. Riley; Alexander M. Sherwood; Chad E. Groer; Nirajmohan Shivaperumal; Miguel Biscaia; Kelly Paton; Sebastian Schneider; Davide Provasi; Bronwyn M. Kivell; Marta Filizola; Thomas E. Prisinzano

doi:10.1021/acs.jmedchem.6b01235

Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability

Rachel Saylor Crowley, Andrew P. Riley, Alexander M. Sherwood, Chad E. Groer, Nirajmohan Shivaperumal, Miguel Biscaia, Kelly Paton, Sebastian Schneider, Davide Provasi, Bronwyn M. Kivell, Marta Filizola, Thomas E. Prisinzano

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

36 Scopus citations

Abstract

Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective μ-opioid receptor (MOR) agonist (EC₅₀ = 1.2 nM, >8000 μ/κ selectivity). 5 is a biased activator of MOR-induced G-protein signaling over β-arrestin-2 recruitment. Metadynamics simulations of 5's binding to a MOR crystal structure suggest energetically preferred binding modes that differ from crystallographic ligands. In vivo studies with 5 demonstrate centrally mediated antinociception, significantly reduced rewarding effects, tolerance, and sedation. We propose that this novel MOR agonist may represent a valuable tool in distinguishing the pathways involved in MOR-induced analgesia from its side effects.

Original language	English
Pages (from-to)	11027-11038
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	24
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01235
State	Published - Dec 22 2016

Bibliographical note

Funding Information:
This work was supported by DA018151 and GM111385 (to T.E.P.), DA03049, MH107053, and DA026434 (to M.F.), GM008545 (to A.P.R. and R.S.C.), AFPE Predoctoral Fellowship in Pharmaceutical Sciences (to R.S.C.), and the Neurological Foundation and Health Research Council of New Zealand and Victoria University of Wellington (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.

Publisher Copyright:
© 2016 American Chemical Society.

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.6b01235

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Crowley, R. S., Riley, A. P., Sherwood, A. M., Groer, C. E., Shivaperumal, N., Biscaia, M., Paton, K., Schneider, S., Provasi, D., Kivell, B. M., Filizola, M., & Prisinzano, T. E. (2016). Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability. Journal of Medicinal Chemistry, 59(24), 11027-11038. https://doi.org/10.1021/acs.jmedchem.6b01235

@article{fd4062da4d014a3f8cab11aa8f44da94,

title = "Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability",

abstract = "Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective μ-opioid receptor (MOR) agonist (EC50 = 1.2 nM, >8000 μ/κ selectivity). 5 is a biased activator of MOR-induced G-protein signaling over β-arrestin-2 recruitment. Metadynamics simulations of 5's binding to a MOR crystal structure suggest energetically preferred binding modes that differ from crystallographic ligands. In vivo studies with 5 demonstrate centrally mediated antinociception, significantly reduced rewarding effects, tolerance, and sedation. We propose that this novel MOR agonist may represent a valuable tool in distinguishing the pathways involved in MOR-induced analgesia from its side effects.",

author = "Crowley, {Rachel Saylor} and Riley, {Andrew P.} and Sherwood, {Alexander M.} and Groer, {Chad E.} and Nirajmohan Shivaperumal and Miguel Biscaia and Kelly Paton and Sebastian Schneider and Davide Provasi and Kivell, {Bronwyn M.} and Marta Filizola and Prisinzano, {Thomas E.}",

note = "Funding Information: This work was supported by DA018151 and GM111385 (to T.E.P.), DA03049, MH107053, and DA026434 (to M.F.), GM008545 (to A.P.R. and R.S.C.), AFPE Predoctoral Fellowship in Pharmaceutical Sciences (to R.S.C.), and the Neurological Foundation and Health Research Council of New Zealand and Victoria University of Wellington (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. Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

year = "2016",

month = dec,

day = "22",

doi = "10.1021/acs.jmedchem.6b01235",

language = "English",

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Crowley, RS, Riley, AP, Sherwood, AM, Groer, CE, Shivaperumal, N, Biscaia, M, Paton, K, Schneider, S, Provasi, D, Kivell, BM, Filizola, M & Prisinzano, TE 2016, 'Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability', Journal of Medicinal Chemistry, vol. 59, no. 24, pp. 11027-11038. https://doi.org/10.1021/acs.jmedchem.6b01235

Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability. / Crowley, Rachel Saylor; Riley, Andrew P.; Sherwood, Alexander M. et al.
In: Journal of Medicinal Chemistry, Vol. 59, No. 24, 22.12.2016, p. 11027-11038.

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

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T1 - Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum

T2 - Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability

AU - Crowley, Rachel Saylor

AU - Riley, Andrew P.

AU - Sherwood, Alexander M.

AU - Groer, Chad E.

AU - Shivaperumal, Nirajmohan

AU - Biscaia, Miguel

AU - Paton, Kelly

AU - Schneider, Sebastian

AU - Provasi, Davide

AU - Kivell, Bronwyn M.

AU - Filizola, Marta

AU - Prisinzano, Thomas E.

N1 - Funding Information: This work was supported by DA018151 and GM111385 (to T.E.P.), DA03049, MH107053, and DA026434 (to M.F.), GM008545 (to A.P.R. and R.S.C.), AFPE Predoctoral Fellowship in Pharmaceutical Sciences (to R.S.C.), and the Neurological Foundation and Health Research Council of New Zealand and Victoria University of Wellington (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. Publisher Copyright: © 2016 American Chemical Society.

PY - 2016/12/22

Y1 - 2016/12/22

N2 - Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective μ-opioid receptor (MOR) agonist (EC50 = 1.2 nM, >8000 μ/κ selectivity). 5 is a biased activator of MOR-induced G-protein signaling over β-arrestin-2 recruitment. Metadynamics simulations of 5's binding to a MOR crystal structure suggest energetically preferred binding modes that differ from crystallographic ligands. In vivo studies with 5 demonstrate centrally mediated antinociception, significantly reduced rewarding effects, tolerance, and sedation. We propose that this novel MOR agonist may represent a valuable tool in distinguishing the pathways involved in MOR-induced analgesia from its side effects.

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Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability

Abstract

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