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 journalArticlepeer-review

26 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 languageEnglish
Pages (from-to)1781-1790
Number of pages10
JournalACS Chemical Neuroscience
Volume11
Issue number12
DOIs
StatePublished - Jun 17 2020

Bibliographical note

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

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this