title: Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist.
abstract: Orexins/hypocretins are key neuropeptides responsible for regulating central arousal and reward circuits. Two receptors respond to orexin signaling, orexin 1 receptor (OX(1)R) and orexin 2 receptor (OX(2)R) with partially overlapping nervous system distributions. Genetic studies suggest orexin receptor antagonists could be therapeutic for insomnia and other disorders with disruptions of sleep and wake. Suvorexant (MK-4305) is a potent, selective, and orally bioavailable antagonist of OX(1)R and OX(2)R currently under clinical investigation as a novel therapy for insomnia. Examination of Suvorexant in radioligand binding assays using tissue from transgenic rats expressing the human OX(2)R found nearly full receptor occupancy (>90%) at plasma exposures of 1.1 μM. Dosed orally Suvorexant significantly and dose-dependently reduced locomotor activity and promoted sleep in rats (10, 30, and 100 mg/kg), dogs (1 and 3 mg/kg), and rhesus monkeys (10 mg/kg). Consistent cross-species sleep/wake architecture changes produced by Suvorexant highlight a unique opportunity to develop dual orexin antagonists as a novel therapy for insomnia.
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
authors.forename: Scott M
authors.initials: SM
authors.lastname: Doran
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Tannenbaum
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Breslin
authors.forename: Susan L
authors.initials: SL
authors.lastname: Garson
authors.forename: Steven V
authors.initials: SV
authors.lastname: Fox
authors.forename: Charles M
authors.initials: CM
authors.lastname: Harrell
authors.forename: Joanne
authors.initials: J
authors.lastname: Stevens
authors.forename: Duane R
authors.initials: DR
authors.lastname: Reiss
authors.forename: Donghui
authors.initials: D
authors.lastname: Cui
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001381:Azepines / Q000494:pharmacology*; D001386:Azides; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004576:Electromyography; D006801:Humans; D008253:Macaca mulatta; D009043:Motor Activity / Q000187:drug effects; D015282:Octreotide / Q000031:analogs & derivatives; D064446:Orexin Receptors; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012890:Sleep / Q000187:drug effects*; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D001381:Azepines; D001386:Azides; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014230:Triazoles; C551624:suvorexant; C074329:EE 581; D015282:Octreotide