Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists

Bioorg Med Chem. 2014 Aug 1;22(15):4067-72. doi: 10.1016/j.bmc.2014.05.065. Epub 2014 Jun 12.

Abstract

Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse.

Keywords: Antagonist; Naltrexone; Non-selective; Opioid; Partial agonist.

Publication types

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

MeSH terms

  • Analgesics, Opioid / chemical synthesis
  • Analgesics, Opioid / chemistry
  • Analgesics, Opioid / metabolism
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Humans
  • Kinetics
  • Morphinans / chemical synthesis
  • Morphinans / chemistry*
  • Morphinans / metabolism
  • Protein Binding
  • Pyridines / chemistry*
  • Pyrroles / chemistry*
  • Receptors, Opioid, delta / agonists*
  • Receptors, Opioid, delta / genetics
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, mu / agonists*
  • Receptors, Opioid, mu / genetics
  • Receptors, Opioid, mu / metabolism
  • Structure-Activity Relationship

Substances

  • Analgesics, Opioid
  • Morphinans
  • Pyridines
  • Pyrroles
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • pyridine