The Replacement of the 2-methoxy Substituent of N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine Improves the Selectivity for 5-HT 1A Receptor Over α 1-adrenoceptor and D 2-like Receptor Subtypes

Eur J Med Chem. 2017 Jan 5;125:233-244. doi: 10.1016/j.ejmech.2016.09.026. Epub 2016 Sep 9.

Abstract

N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine (3) is a potent 5-HT1A receptor and α1d-adrenoceptor (α1d-AR) ligand. Analogues 5-10 were rationally designed and prepared to evaluate whether electronic and/or lipophilic properties of substituents in the ortho position of its phenoxy moiety exert any favorable effects on the affinity/activity at 5-HT1A receptor and improve selectivity over α1-ARs. To rationalize the experimental observations and derive information about receptor-ligand interactions of the reported ligands, docking studies, using 5-HT1A and α1d-AR models generated by homology techniques, and a retrospective computational study were performed. The results highlighted that proper substituents in position 2 of the phenoxy moiety of 3 selectively address the ligands toward 5-HT1A receptor with respect to α1-ARs and D2-like receptor subtypes. Methoxymethylenoxy derivative 9 showed the best 5-HT1A selectivity profile and the highest potency at 5-HT1A receptor, behaving as a partial agonist. Finally, 9, tested in light/dark exploration test in mice, significantly reduced anxiety-linked behaviors. Therefore, it may be considered a lead for the design of partial agonists potentially useful in the treatment of disorders in which 5-HT1A receptor is involved.

Keywords: 5-HT(1A) receptor; Anxiolytic effect; D(2)-like receptor subtypes; Docking studies; Selective 5-HT(1A) receptor agonists; α(1)-Adrenoceptor subtypes.

MeSH terms

  • Amines / metabolism*
  • Animals
  • Anti-Anxiety Agents / chemistry
  • Anti-Anxiety Agents / pharmacology
  • Anxiety / drug therapy
  • Dioxanes / metabolism*
  • Ethylamines / metabolism*
  • Ligands
  • Mice
  • Molecular Docking Simulation
  • Receptor, Serotonin, 5-HT1A / drug effects
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Receptors, Adrenergic, alpha-1 / drug effects
  • Receptors, Adrenergic, alpha-1 / metabolism*
  • Retrospective Studies
  • Structure-Activity Relationship

Substances

  • Amines
  • Anti-Anxiety Agents
  • Dioxanes
  • Ethylamines
  • Ligands
  • N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-(methoxymethoxy)phenoxy)ethanamine
  • N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine
  • Receptors, Adrenergic, alpha-1
  • Receptor, Serotonin, 5-HT1A