Effects of N-Substitutions on the Tetrahydroquinoline (THQ) Core of Mixed-Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Ligands

J Med Chem. 2016 May 26;59(10):4985-98. doi: 10.1021/acs.jmedchem.6b00308. Epub 2016 May 16.

Abstract

N-Acetylation of the tetrahydroquinoline (THQ) core of a series of μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist ligands increases DOR affinity, resulting in ligands with balanced MOR and DOR affinities. We report a series of N-substituted THQ analogues that incorporate various carbonyl-containing moieties to maintain DOR affinity and define the steric and electronic requirements of the binding pocket across the opioid receptors. 4h produced in vivo antinociception (ip) for 1 h at 10 mg/kg.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Molecular Conformation
  • Quinolines / chemical synthesis
  • Quinolines / chemistry*
  • Quinolines / pharmacology*
  • Rats
  • Receptors, Opioid, delta / antagonists & inhibitors*
  • Receptors, Opioid, mu / agonists*
  • Structure-Activity Relationship

Substances

  • Ligands
  • Quinolines
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • 1,2,3,4-tetrahydroquinoline