O6C-20-nor-salvinorin A is a stable and potent KOR agonist

Bioorg Med Chem Lett. 2018 Sep 1;28(16):2770-2772. doi: 10.1016/j.bmcl.2018.01.055. Epub 2018 Jan 31.

Abstract

Salvinorin A (SalA) is a potent and selective agonist of the kappa-opioid receptor (KOR), but its instability has frustrated medicinal chemistry efforts. Treatment of SalA with weak bases like DBU leads to C8 epimerization with loss of receptor affinity and signaling potency. Here we show that replacement of C20 with H and replacement of O6 with CH2 stabilizes the SalA scaffold relative to its C8 epimer, so much so that epimerization is completely supressed. This new compound, O6C-20-nor-SalA, retains high potency for agonism of KOR.

Keywords: Conformational analysis; Heck reaction; Kappa opioid receptor; Salvinorin; Total synthesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carbon / chemistry
  • Carbon / pharmacology*
  • Diterpenes, Clerodane / chemical synthesis
  • Diterpenes, Clerodane / chemistry
  • Diterpenes, Clerodane / pharmacology*
  • Humans
  • Molecular Conformation
  • Oxygen / chemistry
  • Oxygen / pharmacology*
  • Receptors, Opioid, kappa / agonists*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Diterpenes, Clerodane
  • Receptors, Opioid, kappa
  • Carbon
  • Oxygen
  • salvinorin A