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Orexin OX2 Receptor Antagonists as Sleep Aids

  • Laura H. Jacobson
  • Sui Chen
  • Sanjida Mir
  • Daniel Hoyer
Chapter
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 33)

Abstract

The discovery of the orexin system represents the single major progress in the sleep field of the last three to four decades. The two orexin peptides and their two receptors play a major role in arousal and sleep/wake cycles. Defects in the orexin system lead to narcolepsy with cataplexy in humans and dogs and can be experimentally reproduced in rodents. At least six orexin receptor antagonists have reached Phase II or Phase III clinical trials in insomnia, five of which are dual orexin receptor antagonists (DORAs) that target both OX1 and OX2 receptors (OX2Rs). All clinically tested DORAs induce and maintain sleep: suvorexant, recently registered in the USA and Japan for insomnia, represents the first hypnotic principle that acts in a completely different manner from the current standard medications. It is clear, however, that in the clinic, all DORAs promote sleep primarily by increasing rapid eye movement (REM) and are almost devoid of effects on slow-wave (SWS) sleep. At present, there is no consensus on whether the sole promotion of REM sleep has a negative impact in patients suffering from insomnia. However, sleep onset REM (SOREM), which has been documented with DORAs, is clearly an undesirable effect, especially for narcoleptic patients and also in fragile populations (e.g. elderly patients) where REM-associated loss of muscle tone may promote an elevated risk of falls. Debate thus remains as to the ideal orexin agent to achieve a balanced increase in REM and non-rapid eye movement (NREM) sleep. Here, we review the evidence that an OX2R antagonist should be at least equivalent, or perhaps superior, to a DORA for the treatment of insomnia. An OX2R antagonist may produce more balanced sleep than a DORA. Rodent sleep experiments show that the OX2R is the primary target of orexin receptor antagonists in sleep modulation. Furthermore, an OX2R antagonist should, in theory, have a lower narcoleptic/cataplexic potential. In the clinic, the situation remains equivocal, since OX2R antagonists are in early stages: MK-1064 has completed Phase I, and MIN202 is currently in clinical Phase II/III trials. However, data from insomnia patients have not yet been released. Promotional material suggests that balanced sleep is indeed induced by MIN-202, whereas in volunteers MK-1064 has been reported to act similarly to DORAs.

Keywords

Insomnia NREM sleep Orexin receptor antagonist OX2REM sleep 

Abbreviations

2-SORA

Selective orexin 2 receptor antagonist

BNST

Bed nucleus of the stria terminalis

CHMP

Committee for Medicinal Products for Human Use

CNS

Central nervous system

CSF

Cerebrospinal fluid

DMH

Dorsomedial hypothalamic nuclei

DORA

Dual orexin receptor antagonist

DOX

Doxycycline

DR

Dorsal raphe

DREADDs

Designer receptors exclusively activated by designer drugs

DREM

Direct transitions between wake and REM sleep

DSM-IV/DSM-V

Diagnostic and Statistical Manual of Mental Disorders Fourth/Fifth edition

DTA mice

Mice in which selective orexin neuron loss is engineered by inducible expression of diphtheria toxin A

EDS

Excessive daytime sleepiness

EMA

European Medicines Agency

FDA

US Food and Drug Administration

GABAAR

Gamma-aminobutyric acid A receptor

HCRT

Hypocretin

ICV

Intracerebroventricular

KO

Knockout

LC

Locus coeruleus

LDT

Laterodorsal tegmental nucleus

LH

Lateral hypothalamus

LPT

Lateral pontine tegmentum

MnPO

Median preoptic nucleus

NREM

Non-rapid eye movement sleep

OX

Orexin

OXR

Orexin receptor

OX1R

Orexin 1 receptor

OX2R

Orexin 2 receptor

PB

Parabrachial nucleus

PC

Precoeruleus

PPT

Pedunculopontine tegmental area

PSG

Polysomnography

REM

Rapid eye movement sleep

SCN

Suprachiasmatic nucleus

SORA

Selective orexin receptor antagonist

SOREM

Sleep onset REM

SLD

Sublaterodorsal nucleus

SWS

Slow-wave sleep

TMN

Tuberomammillary nucleus

TST

Total sleep time

vlPAG

Ventrolateral periaqueductal grey

VLPO

Ventrolateral preoptic area

vPAG

Ventral periaqueductal grey

VTA

Ventral tegmental area

WASO

Wake after sleep onset

WT

Wild type

Z drugs

Non-benzodiazepine site GABAA receptor positive allosteric modulators; the current market-leading hypnotics (zopiclone, zolpidem, eszopiclone, zaleplon)

ZT

Zeitgeber time (ZT0 and ZT24 = lights on, ZT12 = lights off)

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Authors and Affiliations

  • Laura H. Jacobson
    • 1
    • 2
  • Sui Chen
    • 2
  • Sanjida Mir
    • 2
  • Daniel Hoyer
    • 1
    • 2
    • 3
  1. 1.The Florey Institute of Neuroscience and Mental HealthThe University of MelbourneParkvilleAustralia
  2. 2.Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health SciencesThe University of MelbourneParkvilleAustralia
  3. 3.Department of Chemical PhysiologyThe Scripps Research InstituteLa JollaUSA

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