title: Conformational analysis of N,N-disubstituted-1,4-diazepane orexin receptor antagonists and implications for receptor binding.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. chris_cox@merck.com
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bogusky
authors.forename: David B
authors.initials: DB
authors.lastname: Whitman
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ball
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
mesh_terms: 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
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D047028:Macrocyclic Compounds; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide