ArticleBMC neuroscience2013
The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold.
Article in BMC neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
45 citing papers in PubMed, 94 citations in OpenAlex.
- Long-Term Safety and Tolerability of Daridorexant in Patients with Insomnia Disorder.CNS drugs · 2023Trial
- Effects of TS-142, a novel dual orexin receptor antagonist, on sleep in patients with insomnia: a randomized, double-blind, placebo-controlled phase 2 study.Psychopharmacology · 2022Trial
- Pharmacokinetics, Pharmacodynamics, and Safety of the Dual Orexin Receptor Antagonist Lemborexant: Findings From Single-Dose and Multiple-Ascending-Dose Phase 1 Studies in Healthy Adults.Clinical pharmacology in drug development · 2021Trial
- Safety, Tolerability, and Pharmacokinetics of Suvorexant: A Randomized Rising-Dose Trial in Healthy Men.Clinical drug investigation · 2018Trial
- Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man.Scientific reports · 2016Trial
- Trial
- Selective orexin receptor cross-over treatment increases resilience and expression of neuroplastic signaling genes.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- Article
- Effects of an orexin receptor 2-selective agonist on salivary secretion in rats.Scientific reports · 2026Article
- Estimation of the Orexin Receptor Occupancy From Human Plasma Pharmacokinetics of Vornorexant, a Novel Dual Orexin 1/2 Receptor Antagonist for the Treatment of Insomnia.Pharmacology research & perspectives · 2026Article
- Orexin concentrations and diurnal variation in the cerebrospinal fluid of intensive care unit patients undergoing aortic surgery with spinal drainage.Neuropsychopharmacology reports · 2025Article
- Effects of methamphetamine on actigraphy-based sleep parameters in female rhesus monkeys: Orexin receptor mechanisms.Drug and alcohol dependence · 2024Article
- Pyrazole derivatives as selective orexin-2 receptor antagonists (2-SORA): synthesis, structure-activity-relationship, and sleep-promoting properties in rats.RSC medicinal chemistry · 2024Article
- Article
- Daily treatment with the dual orexin receptor antagonist DORA-12 during oxycodone abstinence decreases oxycodone conditioned reinstatement.Neuropharmacology · 2023Article
- Daridorexant, a Recently Approved Dual Orexin Receptor Antagonists (DORA) in Treatment of Insomnia.Sleep science (Sao Paulo, Brazil) · 2023Article
- Diurnal Fluctuations of Orexin-A and -B in Cynomolgus Monkey Cerebrospinal Fluid Determined by a Novel Analytical Method Using Antiadsorptive Additive Treatment Followed by Nanoflow Liquid Chromatography-High-Resolution Mass Spectrometry.ACS chemical neuroscience · 2023Article
- Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats.Frontiers in pharmacology · 2023Article
- Dual Orexin Receptor Antagonist Attenuates Increases in IOP, ICP, and Translaminar Pressure Difference After Stimulation of the Hypothalamus in Rats.Investigative ophthalmology & visual science · 2022Article
- What evidence is there for implicating the brain orexin system in neuropsychiatric symptoms in dementia?Frontiers in psychiatry · 2022Article
Corrections and comments
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Authors and funding
20 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundDrugs targeting insomnia ideally promote sleep throughout the night, maintain normal sleep architecture, and are devoid of residual effects associated with morning sedation. These features of an ideal compound are not only dependent upon pharmacokinetics, receptor binding kinetics, potency and pharmacodynamic activity, but also upon a compound's mechanism of action.
resultsDual orexin receptor antagonists (DORAs) block the arousal-promoting activity of orexin peptides and, as demonstrated in the current work, exhibit an efficacy signal window dependent upon oscillating levels of endogenous orexin neuropeptide. Sleep efficacy of structurally diverse DORAs in rat and dog was achieved at plasma exposures corresponding to orexin 2 receptor (OX2R) occupancies in the range of 65 to 80%. In rats, the time course of OX2R occupancy was dependent upon receptor binding kinetics and was tightly correlated with the timing of active wake reduction. In rhesus monkeys, direct comparison of DORA-22 with GABA-A modulators at similar sleep-inducing doses revealed that diazepam produced next-day residual sleep and both diazepam and eszopiclone induced next-day cognitive deficits. In stark contrast, DORA-22 did not produce residual effects. Furthermore, DORA-22 evoked only minimal changes in quantitative electroencephalogram (qEEG) activity during the normal resting phase in contrast to GABA-A modulators which induced substantial qEEG changes.
conclusionThe higher levels of receptor occupancy necessary for DORA efficacy require a plasma concentration profile sufficient to maintain sleep for the duration of the resting period. DORAs, with a half-life exceeding 8 h in humans, are expected to fulfill this requirement as exposures drop to sub-threshold receptor occupancy levels prior to the wake period, potentially avoiding next-day residual effects at therapeutic doses.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.