ArticlePloS one2012
Dual hypocretin receptor antagonism is more effective for sleep promotion than antagonism of either receptor alone.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 121 citations in OpenAlex.
- Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man.Scientific reports · 2016Trial
- Therapeutic potential of targeting the orexin (hypocretin) system in sleep disorders.Nature reviews. Endocrinology · 2026Review
- Current and novel dual orexin receptor antagonists for the treatment of insomnia: the emergence of vornorexant.The international journal of neuropsychopharmacology · 2025Review
- Emerging medications and pharmacological treatment approaches for substance use disorders.Pharmacology, biochemistry, and behavior · 2025Review
- Signal transduction, dimerization, and therapeutic targeting of Orexin and receptor systems.Frontiers in pharmacology · 2025Review
- Readjustment of circadian clocks by exercise intervention is a potential therapeutic target for sleep disorders: a narrative review.Physical activity and nutrition · 2024Article
- Effects of methamphetamine on actigraphy-based sleep parameters in female rhesus monkeys: Orexin receptor mechanisms.Drug and alcohol dependence · 2024Article
- Effects of single and dual hypocretin-receptor blockade or knockdown of hypocretin projections to the central amygdala on alcohol drinking in dependent male rats.Addiction neuroscience · 2022Article
- The dual orexin receptor antagonist almorexant blocks the sleep-disrupting and daytime stimulant effects of methamphetamine in rhesus monkeys.Drug and alcohol dependence · 2021Article
- At the intersection of sleep deficiency and opioid use: mechanisms and therapeutic opportunities.Translational research : the journal of laboratory and clinical medicine · 2021Review
- Discovery of Arylsulfonamides as Dual Orexin Receptor Agonists.Journal of medicinal chemistry · 2021Article
- Circadian rhythm as a therapeutic target.Nature reviews. Drug discovery · 2021Review
- Hypocretin/Orexin Receptor Pharmacology and Sleep Phases.Frontiers of neurology and neuroscience · 2021Review
- Population Pharmacokinetics and Exposure-Response Analyses for the Most Frequent Adverse Events Following Treatment With Lemborexant, an Orexin Receptor Antagonist, in Subjects With Insomnia Disorder.Journal of clinical pharmacology · 2020Article
- Effects of an Orexin-2 Receptor Antagonist on Sleep and Event-Related Oscillations in Female Rats Exposed to Chronic Intermittent Ethanol During Adolescence.Alcoholism, clinical and experimental research · 2020Article
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- Therapeutics development for addiction: Orexin-1 receptor antagonists.Brain research · 2020Review
- Article
- Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis.Journal of medicinal chemistry · 2020Article
- Dual orexin receptor antagonist induces changes in core body temperature in rats after exercise.Scientific reports · 2019Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The hypocretin (orexin) system is involved in sleep/wake regulation, and antagonists of both hypocretin receptor type 1 (HCRTR1) and/or HCRTR2 are considered to be potential hypnotic medications. It is currently unclear whether blockade of either or both receptors is more effective for promoting sleep with minimal side effects. Accordingly, we compared the properties of selective HCRTR1 (SB-408124 and SB-334867) and HCRTR2 (EMPA) antagonists with that of the dual HCRTR1/R2 antagonist almorexant in the rat. All 4 antagonists bound to their respective receptors with high affinity and selectivity in vitro. Since in vivo pharmacokinetic experiments revealed poor brain penetration for SB-408124, SB-334867 was selected for subsequent in vivo studies. When injected in the mid-active phase, SB-334867 produced small increases in rapid-eye-movement (REM) and non-REM (NR) sleep. EMPA produced a significant increase in NR only at the highest dose studied. In contrast, almorexant decreased NR latency and increased both NR and REM proportionally throughout the subsequent 6 h without rebound wakefulness. The increased NR was due to a greater number of NR bouts; NR bout duration was unchanged. At the highest dose tested (100 mg/kg), almorexant fragmented sleep architecture by increasing the number of waking and REM bouts. No evidence of cataplexy was observed. HCRTR1 occupancy by almorexant declined 4-6 h post-administration while HCRTR2 occupancy was still elevated after 12 h, revealing a complex relationship between occupancy of HCRT receptors and sleep promotion. We conclude that dual HCRTR1/R2 blockade is more effective in promoting sleep than blockade of either HCRTR alone. In contrast to GABA receptor agonists which induce sleep by generalized inhibition, HCRTR antagonists seem to facilitate sleep by reducing waking "drive".
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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.