Structure-activity Relationships in 1,4-benzodioxan-related Compounds. 9. From 1,4-benzodioxane to 1,4-dioxane Ring as a Promising Template of Novel alpha1D-adrenoreceptor Antagonists, 5-HT1A Full Agonists, and Cytotoxic Agents

J Med Chem. 2008 Oct 23;51(20):6359-70. doi: 10.1021/jm800461k. Epub 2008 Sep 26.

Abstract

Novel 1,4-dioxane compounds structurally related to WB 4101 (1) were prepared in order to investigate the possibility that the quite planar 1,4-benzodioxane template of 1 might be replaced by the less conformationally constrained 1,4-dioxane ring. The biological profiles of the new compounds were assessed using binding assays at human cloned alpha 1-adrenoreceptor (alpha 1-AR) subtypes and 5-HT 1A receptors, expressed in Chinese hamster ovary and HeLa cell membranes, respectively, and by functional experiments in isolated rat vas deferens (alpha 1A), spleen (alpha 1B), and aorta (alpha 1D). Moreover, the cytotoxic effects of the novel compounds were determined in PC-3 prostate cancer cells. The results showed that the properly substituted 1,4-dioxane nucleus proved to be a suitable scaffold for selective alpha 1D-AR antagonists (compound 14), potential anticancer agents (compound 13), and full 5-HT 1A receptor agonists (compound 15). In particular, compound 15 may represent a novel lead in the development of highly potent 5-HT 1A receptor full agonists useful as antidepressant and neuroprotective agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists*
  • Benzene / chemistry*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dioxanes / chemistry*
  • Dioxanes / pharmacology*
  • Ethylamines / chemistry*
  • Ethylamines / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Serotonin Receptor Agonists / chemistry*
  • Serotonin Receptor Agonists / pharmacology*
  • Structure-Activity Relationship

Substances

  • ADRA1D protein, human
  • Adra1d protein, rat
  • Adrenergic alpha-1 Receptor Antagonists
  • Dioxanes
  • Ethylamines
  • N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-(methoxymethoxy)phenoxy)ethanamine
  • Receptors, Adrenergic, alpha-1
  • Serotonin Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • Benzene
  • 1,4-dioxane