Orexin (Hypocretin) Receptor Agonists and Antagonists for Treatment of Sleep Disorders

  title={Orexin (Hypocretin) Receptor Agonists and Antagonists for Treatment of Sleep Disorders},
  author={Michihiro Mieda and Takeshi Sakurai},
  journal={CNS Drugs},
Orexin A and orexin B are hypothalamic neuropeptides initially identified as endogenous ligands for two orphan G-protein coupled receptors (GPCRs). They play critical roles in the maintenance of wakefulness by regulating function of monoaminergic and cholinergic neurons that are implicated in the regulation of wakefulness. Loss of orexin neurons in humans is associated with narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy, further suggesting the… 

The roles of orexins in sleep/wake regulation

Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders

ORAs have the potential to revolutionize the pharmacological treatment of insomnia because they not only improve sleep, but, in addition, appear to have no dependence – and tolerance-inducing effects, which makes them suitable for long-term-treatment.


Orexin receptor antagonists have no effect on GABA and, instead of promoting sleep, these drugs inactivate wakefulness, which results in improved sleep induction and maintenance parameters without producing impairments in cognitive function and other adverse effects.

Differential Roles of Orexin Receptors in the Regulation of Sleep/Wakefulness

This review presents and discusses the current knowledge concerning the physiological roles of each orexin receptor subtype, focusing on the regulation of sleep/wakefulness.

Effects of a newly developed potent orexin-2 receptor-selective antagonist, compound 1 m, on sleep/wakefulness states in mice

Results suggest that an orexin-mediated suppression of REM sleep via potential activation of OX1Rs in the locus coeruleus may possibly contribute to the differential effects on sleep/wakefulness exerted by a DORA as compared to a 2-SORA.



Promotion of sleep by targeting the orexin system in rats, dogs and humans

In rats, dogs and humans, somnolence is induced by pharmacological blockade of both orexin OX1 and OX2 receptors, and this results open new perspectives for investigating the role of endogenous orexins in sleep-wake regulation.

Pharmacological characterization of MK-6096 – A dual orexin receptor antagonist for insomnia

Dual Hypocretin Receptor Antagonism Is More Effective for Sleep Promotion than Antagonism of Either Receptor Alone

It is concluded that dual HCRTR1/R2 blockade is more effective in promoting sleep than blockade of either H CRTR alone.

Arousal effect of orexin A depends on activation of the histaminergic system

  • Zhi-Li HuangW. Qu O. Hayaishi
  • Biology, Psychology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2001
Findings strongly indicate that the arousal effect of orexin A depends on the activation of histaminergic neurotransmission mediated by H1R.

Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice.

Results indicate that orexin neuron-ablated mice retain the ability to respond to orexIn neuropeptides and that a temporally regulated and spatially targeted secretion of orexins is not necessary to prevent narcoleptic symptoms.

Orexin/Hypocretin Excites the Histaminergic Neurons of the Tuberomammillary Nucleus

A functional connection between the two populations of hypothalamic neurons is suggested and that they may cooperate in the regulation of rapid-eye-movement sleep and feeding.

Connectomics of orexin-producing neurons: interface of systems of emotion, energy homeostasis and arousal.

The hypocretin/orexin ligand–receptor system: implications for sleep and sleep disorders

Differential Effects of a Dual Orexin Receptor Antagonist (SB-649868) and Zolpidem on Sleep Initiation and Consolidation, SWS, REM Sleep, and EEG Power Spectra in a Model of Situational Insomnia

This dual orexin receptor antagonist exerts hypnotic activity, with effects on sleep structure and the EEG that are different from those of zolpidem.