Conformational analysis of N,N-disubstituted-1,4-diazepane orexin receptor antagonists and implications for receptor binding

Bioorg Med Chem Lett. 2009 Jun 1;19(11):2997-3001. doi: 10.1016/j.bmcl.2009.04.026. Epub 2009 Apr 14.


NMR spectroscopy, X-ray crystallography, and molecular modeling studies indicate that N,N-disubstituted-1,4-diazepane orexin receptor antagonists exist in an unexpected low-energy conformation that is characterized by an intramolecular pi-stacking interaction and a twist-boat ring conformation. Synthesis and evaluation of a macrocycle that enforces a similar conformation suggest that this geometry mimics the bioactive conformation.

MeSH terms

  • Crystallography, X-Ray
  • Heterocyclic Compounds, 1-Ring / chemical synthesis
  • Heterocyclic Compounds, 1-Ring / chemistry*
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry
  • Magnetic Resonance Spectroscopy
  • Models, Chemical
  • Orexin Receptors
  • Protein Binding
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Receptors, Neuropeptide / metabolism


  • Heterocyclic Compounds, 1-Ring
  • Macrocyclic Compounds
  • Orexin Receptors
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide