Structure-activity Relationships in 1,4-benzodioxan-related Compounds. 11. (1) Reversed Enantioselectivity of 1,4-dioxane Derivatives in α1-adrenergic and 5-HT1A Receptor Binding Sites Recognition

J Med Chem. 2013 Jan 24;56(2):584-8. doi: 10.1021/jm301525w. Epub 2013 Jan 8.

Abstract

5-HT(1A) receptor and α(1)-adrenoreceptor (α(1)-AR) binding sites recognized by the 1,4-dioxanes 2-4 display reversed stereochemical requirements. (S)-2 proved to be a potent 5-HT(1A) receptor agonist highly selective over α(1)-AR subtypes. Chirality influenced the anticancer activity of 3 and 4 in human prostate cancer cells (PC-3): (R)-4, eutomer at the α(1d)-AR subtype, was the most potent. The decreased effect of 4 and (R)-4 in α(1d)-AR silenced PC-3 cells confirmed that their anticancer activity was α(1d)-AR-dependent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line
  • Dioxanes / chemistry
  • Dioxanes / pharmacology*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Receptors, Adrenergic, alpha-1 / drug effects*
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Receptors, Serotonin, 5-HT1 / drug effects*
  • Receptors, Serotonin, 5-HT1 / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Dioxanes
  • Receptors, Adrenergic, alpha-1
  • Receptors, Serotonin, 5-HT1
  • Receptor, Serotonin, 5-HT1A
  • 1,4-benzodioxan