title: Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists.
abstract: 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.
authors.affiliation: Johnson and Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Laura C
authors.initials: LC
authors.lastname: McAtee
authors.forename: Steven W
authors.initials: SW
authors.lastname: Sutton
authors.forename: Dale A
authors.initials: DA
authors.lastname: Rudolph
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Li
authors.forename: Leah E
authors.initials: LE
authors.lastname: Aluisio
authors.forename: Victor K
authors.initials: VK
authors.lastname: Phuong
authors.forename: Curt A
authors.initials: CA
authors.lastname: Dvorak
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
authors.forename: Todd K
authors.initials: TK
authors.lastname: Jones
mesh_terms: D004146:Dioxanes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004146:Dioxanes; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide