Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists

Bioorg Med Chem Lett. 2004 Aug 16;14(16):4225-9. doi: 10.1016/j.bmcl.2004.06.032.


Orexins, also termed hypocretins, consist of two neuropeptide agonists (orexin A and B) interacting with two known G-protein coupled receptors (OX(1)R and OX(2)R). In addition to other biological functions, the orexin-2 receptor is thought to be an important modulator of sleep and wakefulness. Herein we describe a series of novel, selective OX(2)R antagonists consisting of substituted 4-phenyl-[1,3]dioxanes. One such antagonist is compound 9, 1-(2,4-dibromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea, which is bound by the OX(2)R with a pK(i) of 8.3, has a pK(b) of 7.9, and is 600-fold selective for the OX(2)R over the OX(1)R.

MeSH terms

  • Dioxanes / chemistry*
  • Dioxanes / metabolism
  • Dioxanes / pharmacology*
  • Orexin Receptors
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Receptors, Neuropeptide / metabolism


  • Dioxanes
  • Orexin Receptors
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide