Novel substituted 4-phenyl-[1,3]dioxanes: Potent and selective orexin receptor 2 (OX2R) antagonists

Article abstract of 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 ₁R and OX₂R). 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 OX₂R 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 OX₂R with a pK_i of 8.3, has a pK_b of 7.9, and is 600-fold selective for the OX₂R over the OX₁R.