Conformational analysis of N,N-disubstituted-1,4-diazepane orexin receptor antagonists and implications for receptor binding.
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.
Cox
Christopher D
CD
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. chris_cox@merck.com
McGaughey
Georgia B
GB
Bogusky
Michael J
MJ
Whitman
David B
DB
Ball
Richard G
RG
Winrow
Christopher J
CJ
Renger
John J
JJ
Coleman
Paul J
PJ
D018360:Crystallography, X-Ray; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis / Q000737:chemistry*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D064446:Orexin Receptors; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism
D006573:Heterocyclic Compounds, 1-Ring; D047028:Macrocyclic Compounds; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide