Essential structure of orexin 1 receptor antagonist YNT-707, part III: Role of the 14-hydroxy and the 3-methoxy groups in antagonistic activity toward the orexin 1 receptor in YNT-707 derivatives lacking the 4,5-epoxy ring

Bioorg Med Chem. 2019 Apr 15;27(8):1747-1758. doi: 10.1016/j.bmc.2019.03.010. Epub 2019 Mar 5.

Abstract

Morphinan derivatives lacking the 4,5-epoxy ring were synthesized to examine the participation of the 14-OH group, the 3-OMe group, and the aromaticity of the A-ring in the activity and selectivity for the orexin 1 receptor (OX1R). The assay results and the conformational analyses of the 14-dehydrated and 14-H derivatives suggested that the orientations of the 6-amide side chain and the 17-benzenesulfonyl group would play important roles in the activity for OX1R. In the 6β-derivatives, removal of the 3-OMe group and the reduction of the A-ring significantly decreased the activity toward the OX1R, but these changes did not affect the 6α-derivatives. These results indicate that the 3-OMe group and the A-ring would be essential structural moieties for the 6β-derivatives.

Keywords: Conformational analysis; Morphinan; OX(1)R antagonist; Orexin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Morphinans / chemistry*
  • Morphinans / pharmacology*
  • Orexin Receptor Antagonists / chemistry*
  • Orexin Receptor Antagonists / pharmacology*
  • Orexin Receptors / chemistry
  • Orexin Receptors / metabolism*
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology*

Substances

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