title: The Discovery of Suvorexant, the First Orexin Receptor Drug for Insomnia.
abstract: Historically, pharmacological therapies have used mechanisms such as γ-aminobutyric acid A (GABAA) receptor potentiation to drive sleep through broad suppression of central nervous system activity. With the discovery of orexin signaling loss as the etiology underlying narcolepsy, a disorder associated with hypersomnolence, orexin antagonism emerged as an alternative approach to attenuate orexin-induced wakefulness more selectively. Dual orexin receptor antagonists (DORAs) block the activity of orexin 1 and 2 receptors to both reduce the threshold to transition into sleep and attenuate orexin-mediated arousal. Among DORAs evaluated clinically, suvorexant has pharmacokinetic properties engineered for a plasma half-life appropriate for rapid sleep onset and maintenance at low to moderate doses. Unlike GABAAreceptor modulators, DORAs promote both non-rapid eye movement (NREM) and REM sleep, do not disrupt sleep stage-specific quantitative electroencephalogram spectral profiles, and allow somnolence indistinct from normal sleep. The preservation of cognitive performance and the ability to arouse to salient stimuli after DORA administration suggest further advantages over historical therapies.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486; email: paul_coleman@merck.com.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.affiliation: Department of Clinical Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: W Joseph
authors.initials: WJ
authors.lastname: Herring
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
mesh_terms: D000818:Animals; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D006801:Humans; D000068796:Orexin Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D064446:Orexin Receptors / Q000737:chemistry / Q000502:physiology*; D017433:Protein Structure, Secondary; D000068776:Sleep Aids, Pharmaceutical / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy* / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001381:Azepines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D000068776:Sleep Aids, Pharmaceutical; D014230:Triazoles; C551624:suvorexant
keywords: hyperarousal; insomnia; orexin receptor antagonists; orexins; sleep; suvorexant