Essential structure of orexin 1 receptor antagonist YNT-707, Part II: Drastic effect of the 14-hydroxy group on the orexin 1 receptor antagonistic activity

Bioorg Med Chem Lett. 2018 Feb 15;28(4):774-777. doi: 10.1016/j.bmcl.2017.12.069. Epub 2017 Dec 30.

Abstract

The 14-dehydration- and 14-H derivatives of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) were synthesized. The obtained derivatives showed higher affinities for OX1R than the corresponding 14-hydroxy derivatives. The conformational analysis suggested that the 17-sulfonamide groups in the derivatives without the 14-hydroxy group have a greater tendency to be oriented toward the upper side of the D-ring compared with the 14-hydroxy derivatives. Additionally, the 14-dehydration-derivative with 6α-amide side chain showed significantly higher affinity than the 14-hydroxy derivative, while the corresponding 14-H derivative showed only slightly higher affinity. Thus, the 14-hydroxy group strongly affects the affinity of the antagonist for the OX1R.

Keywords: 4,5-Epoxymorphinan; Conformational study; OX1R antagonist; Orexin; YNT-707.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Molecular Conformation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Morphinans / chemical synthesis
  • Morphinans / chemistry*
  • Orexin Receptor Antagonists / chemical synthesis
  • Orexin Receptor Antagonists / chemistry*
  • Stereoisomerism
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*

Substances

  • Morphinans
  • Orexin Receptor Antagonists
  • Sulfonamides
  • YNT-707