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Behavioral Neuroscience of Orexin/Hypocretin pp 105–136Cite as

Orexin OX2 Receptor Antagonists as Sleep Aids

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Part of the book series: Current Topics in Behavioral Neurosciences ((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.

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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

  1. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia

    Laura H. Jacobson & Daniel Hoyer

  2. Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia

    Laura H. Jacobson, Sui Chen, Sanjida Mir & Daniel Hoyer

  3. Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA, 92037, USA

    Daniel Hoyer

Authors
  1. Laura H. Jacobson
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  2. Sui Chen
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  3. Sanjida Mir
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  4. Daniel Hoyer
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Corresponding author

Correspondence to Daniel Hoyer .

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Editors and Affiliations

  1. Florey Institute of Neuroscience & Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia

    Andrew J Lawrence

  2. Dep Psychiatry & Behav Sciences, Stanford University, Stanford, CA, USA

    Luis de Lecea

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Jacobson, L.H., Chen, S., Mir, S., Hoyer, D. (2016). Orexin OX2 Receptor Antagonists as Sleep Aids. In: Lawrence, A.J., de Lecea, L. (eds) Behavioral Neuroscience of Orexin/Hypocretin. Current Topics in Behavioral Neurosciences, vol 33. Springer, Cham. https://doi.org/10.1007/7854_2016_47

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