14-O-Heterocyclic-substituted naltrexone derivatives as non-peptide mu opioid receptor selective antagonists: design, synthesis, and biological studies

Bioorg Med Chem Lett. 2009 Mar 15;19(6):1825-9. doi: 10.1016/j.bmcl.2008.12.093. Epub 2008 Dec 29.

Abstract

Mu opioid receptor antagonists have clinical utility and are important research tools. To develop non-peptide and highly selective mu opioid receptor antagonist, a series of 14-O-heterocyclic-substituted naltrexone derivatives were designed, synthesized, and evaluated. These compounds showed subnanomolar-to-nanomolar binding affinity for the mu opioid receptor. Among them, compound 1 exhibited the highest selectivity for the mu opioid receptor over the delta and kappa receptors. These results implicated an alternative 'address' domain in the extracellular loops of the mu opioid receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • Chemistry, Pharmaceutical / methods*
  • Drug Design
  • Humans
  • Kinetics
  • Ligands
  • Molecular Conformation
  • Molecular Structure
  • Naltrexone / analogs & derivatives*
  • Narcotic Antagonists / chemical synthesis*
  • Narcotic Antagonists / pharmacology
  • Nitrogen / chemistry
  • Peptides / chemistry
  • Protein Structure, Tertiary
  • Receptors, Opioid, mu / antagonists & inhibitors*
  • Receptors, Opioid, mu / chemistry*

Substances

  • Ligands
  • Narcotic Antagonists
  • Peptides
  • Receptors, Opioid, mu
  • Naltrexone
  • Nitrogen