Discovery of highly selective κ-opioid receptor agonists: 10α-Hydroxy TRK-820 derivatives

Bioorg Med Chem Lett. 2017 Aug 15;27(16):3920-3924. doi: 10.1016/j.bmcl.2017.06.017. Epub 2017 Jun 12.

Abstract

κ-Opioid receptor agonists with high selectivity over the μ-opioid receptor are attractive targets in the development of drugs for pain and pruritus. We previously reported the synthesis of 10α-hydroxy TRK-820 (1). In this study, we elucidated the biological properties of 1 and optimized its 6-acyl unit by modifying our synthetic route. Among the 10α-hydroxy TRK-820 derivatives prepared, 26 showed the most potent κ-opioid agonist activity (EC50=0.00466nM) and excellent selectivity and 22 was the most κ-selective agonist.

Keywords: 4,5-Epoxymorphinan; Analgesic; Antipruritic; TRK-820; κ-Opioid receptor; μ-Opioid receptor.

MeSH terms

  • Analgesics / administration & dosage
  • Analgesics / chemistry
  • Analgesics / pharmacology*
  • Animals
  • Behavior, Animal / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Mice
  • Molecular Structure
  • Morphinans / administration & dosage
  • Morphinans / chemistry
  • Morphinans / pharmacology*
  • Neuralgia / drug therapy*
  • Rats
  • Receptors, Opioid, kappa / agonists*
  • Spiro Compounds / administration & dosage
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship
  • Substance P / administration & dosage
  • Substance P / pharmacology

Substances

  • Analgesics
  • Morphinans
  • Receptors, Opioid, kappa
  • Spiro Compounds
  • TRK 820
  • Substance P