Synthesis of 6,14-epoxymorphinan derivatives and their pharmacologies

Bioorg Med Chem. 2011 Feb 1;19(3):1205-21. doi: 10.1016/j.bmc.2010.12.035. Epub 2010 Dec 21.

Abstract

A novel 6,14-epoxymorphinan benzamide derivative (NS22) that was previously reported showed opioid κ receptor agonistic activity and analgesic activity. The unsatisfactory κ selectivity of NS22 led us to synthesize its derivatives to improve the opioid κ receptor selectivity and the agonist activity. In the course of SAR of the various derivatives, 17-benzyl-6,14-epoxymorphinan derivatives (KNT-33, 53, 55, 80, 90, 133) were found to show high selectivities and affinities for the opioid κ receptor. In addition, KNT-33, 53, 55 showed dose-dependent analgesic effects in acetic acid writhing tests. Therefore, 17-benzyl substituents may play an important role for developing κ selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Analgesics / metabolism
  • Analgesics / pharmacology*
  • Animals
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Drug Design
  • Epoxy Compounds / chemical synthesis*
  • Epoxy Compounds / chemistry
  • Epoxy Compounds / metabolism
  • Epoxy Compounds / pharmacology*
  • Male
  • Mice
  • Molecular Structure
  • Molecular Targeted Therapy
  • Morphinans / chemical synthesis*
  • Morphinans / chemistry
  • Morphinans / metabolism
  • Morphinans / pharmacology*
  • Receptors, Opioid
  • Receptors, Opioid, kappa / agonists*
  • Receptors, Opioid, kappa / metabolism
  • Structure-Activity Relationship

Substances

  • Analgesics
  • Benzamides
  • Epoxy Compounds
  • Morphinans
  • NS22 compound
  • Receptors, Opioid
  • Receptors, Opioid, kappa