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 journalArticlepeer-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 languageEnglish
Pages (from-to)11027-11038
Number of pages12
JournalJournal of Medicinal Chemistry
Volume59
Issue number24
DOIs
StatePublished - 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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