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 GABAA receptor 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 | Paul J Coleman, Anthony L Gotter, W Joseph Herring, Christopher J Winrow, John J Renger |
Journal | Annual review of pharmacology and toxicology
(Annu Rev Pharmacol Toxicol)
Vol. 57
Pg. 509-533
(01 06 2017)
ISSN: 1545-4304 [Electronic] United States |
PMID | 27860547
(Publication Type: Journal Article, Review, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Azepines
- Orexin Receptor Antagonists
- Orexin Receptors
- Sleep Aids, Pharmaceutical
- Triazoles
- suvorexant
|
Topics |
- Animals
- Azepines
(chemistry, pharmacology, therapeutic use)
- Drug Discovery
(methods, trends)
- Humans
- Orexin Receptor Antagonists
(chemistry, pharmacology, therapeutic use)
- Orexin Receptors
(chemistry, physiology)
- Protein Structure, Secondary
- Sleep Aids, Pharmaceutical
(chemistry, pharmacology, therapeutic use)
- Sleep Initiation and Maintenance Disorders
(drug therapy, metabolism)
- Triazoles
(chemistry, pharmacology, therapeutic use)
|