Selective opioid growth factor receptor antagonists based on a stilbene isostere

Bioorg Med Chem. 2017 Aug 15;25(16):4464-4474. doi: 10.1016/j.bmc.2017.06.035. Epub 2017 Jun 27.


As part of an ongoing drug development effort aimed at selective opioid receptor ligands based on the pawhuskin natural products we have synthesized a small set of amide isosteres. These amides were centered on lead compounds which are selective antagonists for the delta and kappa opioid receptors. The amide isomers revealed here show dramatically different activity from the parent stilbene compounds. Three of the isomers synthesized showed antagonist activity for the opioid growth factor (OGF)/opioid growth factor receptor (OGFR) axis which is involved in cellular and organ growth control. This cellular signaling mechanism is targeted by "low-dose" naltrexone therapy which is being tested clinically for multiple sclerosis, Crohn's disease, cancer, and wound healing disorders. The compounds described here are the first selective small molecule ligands for the OGF/OGFR system and will serve as important leads and probes for further study.

Keywords: Low-dose naltrexone; Opioid growth factor; Opioid receptor; Pawhuskin; Stilbene isostere.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Animals
  • COS Cells
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chlorocebus aethiops
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Receptors, Opioid / metabolism*
  • Structure-Activity Relationship


  • Amides
  • Receptors, Opioid
  • methionine-enkephalin receptor