The discovery of suvorexant, the first orexin receptor drug for insomnia

Coleman, Paul J.; Gotter, Anthony L.; Herring, W. Joseph; Winrow, Christopher J.; Renger, John J.

doi:10.1146/annurev-pharmtox-010716-104837

Cited by 131Sleep and Wakefulness ResearchSleep and related disordersCircadian rhythm and melatonin

The discovery of suvorexant, the first orexin receptor drug for insomnia

Coleman, Paul J., Gotter, Anthony L., Herring, W. Joseph, Winrow, Christopher J., Renger, John J.·2017·Annual Review of Pharmacology and Toxicology

DOI 10.1146/annurev-pharmtox-010716-104837

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Abstract

Historically, pharmacological therapies have used mechanisms such as γ-aminobutyric acid A (GABA A ) receptor potentiation to drive sleep through broad suppression of central nervous system activity. With the discovery of orexin signaling loss as the etiology underlying narcolepsy, a disorder associated with hypersomnolence, orexin antagonism emerged as an alternative approach to attenuate orexin-induced wakefulness more selectively. Dual orexin receptor antagonists (DORAs) block the activity of orexin 1 and 2 receptors to both reduce the threshold to transition into sleep and attenuate orexin-mediated arousal. Among DORAs evaluated clinically, suvorexant has pharmacokinetic properties engineered for a plasma half-life appropriate for rapid sleep onset and maintenance at low to moderate doses. Unlike GABA A receptor modulators, DORAs promote both non-rapid eye movement (NREM) and REM sleep, do not disrupt sleep stage–specific quantitative electroencephalogram spectral profiles, and allow somnolence indistinct from normal sleep. The preservation of cognitive performance and the ability to arouse to salient stimuli after DORA administration suggest further advantages over historical therapies.

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Orexin Receptor Antagonism, a New Sleep-Enabling Paradigm: A Proof-of-Concept Clinical Trial
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Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis
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Orexin / hypocretin 1 receptor antagonist reduces heroin self‐administration and cue‐induced heroin seeking
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Orexin (hypocretin)/dynorphin neurons control GABAergic inputs to tuberomammillary neurons
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Activation of the orexin 1 receptor is a critical component of CO2-mediated anxiety and hypertension but not bradycardia
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A Selective Orexin-1 Receptor Antagonist Attenuates Stress-Induced Hyperarousal without Hypnotic Effects
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Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist
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Microinjection of orexin into the rat nucleus tractus solitarius causes increases in blood pressure
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Orexin signaling in recombinant neuron‐like cells
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Discovery of a Potent, CNS‐Penetrant Orexin Receptor Antagonist Based on an N,N‐Disubstituted‐1,4‐diazepane Scaffold that Promotes Sleep in Rats
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Point mutations of the alpha 1 beta 2 gamma 2 gamma-aminobutyric acid(A) receptor affecting modulation of the channel by ligands of the benzodiazepine binding site.
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Discovery of 5′′‐Chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064): A Selective Orexin 2 Receptor Antagonist (2‐SORA) for the Treatment of Insomnia
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Increased orexin levels in the cerebrospinal fluid the first year after a suicide attempt
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Binding kinetics differentiates functional antagonism of orexin‐2 receptor ligands
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OREXIN 1 AND 2 RECEPTOR INVOLVEMENT IN CO 2 -INDUCED PANIC-ASSOCIATED BEHAVIOR AND AUTONOMIC RESPONSES
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Dual orexin receptor antagonist 12 inhibits expression of proteins in neurons and glia implicated in peripheral and central sensitization
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Orexin receptors couple to Ca2+ channels different from store-operated Ca2+ channels
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Almorexant Promotes Sleep and Exacerbates Cataplexy in a Murine Model of Narcolepsy
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Cerebrospinal fluid-orexin levels and sleep attacks in four patients with Parkinson's disease
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Intact learning and memory in rats following treatment with the dual orexin receptor antagonist almorexant
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Neuroendocrine Proopiomelanocortin Neurons Are Excited by Hypocretin/Orexin
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Involvement of TRPC3 channels in calcium oscillations mediated by OX1 orexin receptors
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Inhibition of Orexin Signaling Promotes Sleep Yet Preserves Salient Arousability in Monkeys
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Differential Effects of the Dual Orexin Receptor Antagonist Almorexant and the GABAA-α1 Receptor Modulator Zolpidem, Alone or Combined with Ethanol, on Motor Performance in the Rat
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Electroencephalographic Power Spectral Density Profile of the Orexin Receptor Antagonist Suvorexant in Patients with Primary Insomnia and Healthy Subjects
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Knockdown of orexin type 1 receptor in rat locus coeruleus increases REM sleep during the dark period
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Central benzodiazepine receptor occupancy by zolpidem in the human brain as assessed by positron emission tomography
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Discovery of Dual Orexin Receptor Antagonists (DORAs) for the Treatment of Insomnia
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Novel Octahydropyrrolo[3,4-c]pyrroles Are Selective Orexin-2 Antagonists: SAR Leading to a Clinical Candidate
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Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors
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Structure–Activity Relationship, Biological, and Pharmacological Characterization of the Proline Sulfonamide ACT‐462206: a Potent, Brain‐Penetrant Dual Orexin 1/Orexin 2 Receptor Antagonist
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Dual orexin receptor antagonists show distinct effects on locomotor performance, ethanol interaction and sleep architecture relative to gamma-aminobutyric acid-A receptor modulators
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Quantitative Electroencephalography Within Sleep/Wake States Differentiates GABAA Modulators Eszopiclone and Zolpidem From Dual Orexin Receptor Antagonists in Rats
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The hypocretin/orexin antagonist almorexant promotes sleep without impairment of performance in rats
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Orexin receptor antagonist-induced sleep does not impair the ability to wake in response to emotionally salient acoustic stimuli in dogs
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Both Ox1r and Ox2r orexin receptors contribute to the cardiovascular and locomotor components of the novelty stress response in the rat
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Narcoleptic orexin receptor knockout mice express enhanced cholinergic properties in laterodorsal tegmental neurons
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Discovery of MK-3697: A selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia
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Cardiovascular Actions of Orexin‐A in the Rat Subfornical Organ
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Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists
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Ueber die Verbindungen, welche durch die Einwirkung des Chlors auf Alkohol, Aether, ölbildendes Gas und Essiggeist entstehen
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Discovery and in vitro and in vivo profiles of N-ethyl-N-[2-[3-(5-fluoro-2-pyridinyl)-1H-pyrazol-1-yl]ethyl]-2-(2H-1,2,3-triazol-2-yl)-benzamide as a novel class of dual orexin receptor antagonist
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Orexin/Hypocretin: Wired for Wakefulness
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Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties
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Functional and binding kinetic studies make a distinction between OX1 and OX2 orexin receptor antagonists
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Discovery of HTL6641, a dual orexin receptor antagonist with differentiated pharmacodynamic properties
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The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems
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Sleep Evaluation by Actigraphy for Patients With Alzheimer Disease—Reply
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Ueber die Zersetzung des Alkohols durch Chlor
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Ueber die Verbindungen, welche durch die Einwirkung des Chlors auf Alkohol, Aether, ölbildendes Gas und Essiggeist entstehen
Liebig, J. (1832) · European Journal of Organic Chemistry · doi:10.1002/jlac.1510400203 · Cited by 1 · see citing works

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Optical probing of orexin/hypocretin receptor antagonists
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Molecular mechanism of the wake-promoting agent TAK-925
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The hypocretin/orexin system as a target for excessive motivation in alcohol use disorders
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Early-onset sleep alterations found in patients with amyotrophic lateral sclerosis are ameliorated by orexin antagonist in mouse models
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Rice bran extract supplement improves sleep efficiency and sleep onset in adults with sleep disturbance: A randomized, double-blind, placebo-controlled, polysomnographic study
Um, M. Y., Yang, H., Han, J. K., Kim, J. Y., Kang, S. W., Yoon, M., Kwon, S., & Cho, S. (2019) · Scientific Reports · doi:10.1038/s41598-019-48743-8 · Cited by 28 · see citing works
Translational approaches to influence sleep and arousal
Brown, R. E., Spratt, T. J., & Kaplan, G. B. (2022) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2022.05.002 · Cited by 29 · see citing works
Distinct effects of orexin receptor antagonist and GABA A agonist on sleep and physical/cognitive functions after forced awakening
Seol, J., Fujii, Y., Park, I., Suzuki, Y., Kawana, F., Yajima, K., Fukusumi, S., Okura, T., Satoh, M., Tokuyama, K., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1907354116 · Cited by 28 · see citing works
Effect of gabapentin on sleep and delta and theta EEG power in adult rats exposed to chronic intermittent ethanol vapor and protracted withdrawal during adolescence
Ehlers, C. L., Sánchez-Alavez, M., & Wills, D. N. (2018) · Psychopharmacology · doi:10.1007/s00213-018-4888-6 · Cited by 27 · see citing works
Effect of suvorexant on event-related oscillations and EEG sleep in rats exposed to chronic intermittent ethanol vapor and protracted withdrawal
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Orexins and primary headaches: an overview of the neurobiology and clinical impact
Stanyer, E. C., Hoffmann, J., & Holland, P. R. (2024) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2024.2328728 · Cited by 25 · see citing works
Targeting the Orexin System for Prescription Opioid Use Disorder
Matzeu, A., & Martin‐Fardon, R. (2020) · Brain Sciences · doi:10.3390/brainsci10040226 · Cited by 25 · see citing works
The dual orexinergic receptor antagonist DORA-22 improves the sleep disruption and memory impairment produced by a rodent insomnia model
Gamble, M. C., Katsuki, F., McCoy, J. G., Strecker, R. E., & McKenna, J. T. (2019) · SLEEP · doi:10.1093/sleep/zsz241 · Cited by 25 · see citing works
Pharmacokinetics and Pharmacodynamics of the Dual Orexin Receptor Antagonist Daridorexant in Japanese and Caucasian Subjects
Muehlan, C., Zuiker, R. G. J. A., Peeters, P. A. M., Rowles, R., & Dingemanse, J. (2020) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000001182 · Cited by 25 · see citing works
Pharmacological treatment for insomnia in patients with major depressive disorder
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Safety, Tolerability, and Pharmacokinetics of Suvorexant: A Randomized Rising-Dose Trial in Healthy Men
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Reciprocal relationships between sleep and smell
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Different doses of dual orexin receptor antagonists in primary insomnia: a Bayesian network analysis
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Emerging and upcoming therapies in insomnia
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Effect of CYP3A Inhibition and Induction on the Pharmacokinetics of Suvorexant: Two Phase I, Open-Label, Fixed-Sequence Trials in Healthy Subjects
Wrishko, R. E., McCrea, J. B., Yee, K. L., Liu, W., Panebianco, D. L., Mangin, E. C., Chakravarthy, M. V., Cantarin, M. P. M., & Kraft, W. K. (2019) · Clinical Drug Investigation · doi:10.1007/s40261-019-00764-x · Cited by 21 · see citing works
How well can a large number of polysomnography sleep measures predict subjective sleep quality in insomnia patients?
Svetnik, V., Snyder, E., Tao, P., Roth, T. G., Lines, C., & Herring, W. J. (2019) · Sleep Medicine · doi:10.1016/j.sleep.2019.08.020 · Cited by 20 · see citing works
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The Black Book of Psychotropic Dosing and Monitoring
DeBattista, C., & Schatzberg, A. F. (2025) · Psychopharmacology Bulletin · doi:10.64719/pb.4493 · Cited by 22 · see citing works
Circadian regulation of microglia function: Potential targets for treatment of Parkinson’s Disease
Kou, L., Chi, X., Sun, Y., Yin, S., Wu, J., Zou, W., Wang, Y., Jin, Z., Huang, J., Xiong, N., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102232 · Cited by 20 · see citing works
Role of medial hypothalamic orexin system in panic, phobia and hypertension
de Abreu, A. R. R., Molosh, A. I., Johnson, P. L., & Shekhar, A. (2018) · Brain Research · doi:10.1016/j.brainres.2018.09.010 · Cited by 19 · see citing works
Readjustment of circadian clocks by exercise intervention is a potential therapeutic target for sleep disorders: a narrative review
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The neuropeptidergic connectome of C. elegansPreprint
Ripoll-Sánchez, L., Watteyne, J., Sun, H., Fernandez, R. W., Taylor, S. R., Weinreb, A., Hammarlund, M., Miller, D. M., Hobert, O., Beets, I., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.30.514396 · Cited by 18 · see citing works
Sleep disturbance in substance use disorders: the orexin (hypocretin) system as an emerging pharmacological target
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Neurophysiology and Treatment of Disorders of Consciousness Induced by Traumatic Brain Injury: Orexin Signaling as a Potential Therapeutic Target
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A combinatorial target screening strategy for deorphaning macromolecular targets of natural product
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Palatable food self-administration and reinstatement are not affected by dual orexin receptor antagonism
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Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 1,4-Diazepan-5-ones
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Hypocretin (Orexin) Replacement Therapies
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Essential structure of orexin 1 receptor antagonist YNT-707, Part II: Drastic effect of the 14-hydroxy group on the orexin 1 receptor antagonistic activity
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Effects of Bedtime Dosing With Suvorexant and Zolpidem on Balance and Psychomotor Performance in Healthy Elderly Participants During the Night and in the Morning
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Network pharmacology and pharmacological evaluation for deciphering novel indication of Sishen Wan in insomnia treatment
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Comparison of polysomnography in people with Alzheimer's disease and insomnia versus non-demented elderly people with insomnia
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The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanylPreprint
O’Connor, S. L., Fragale, J. E. C., James, M. H., & Aston‐Jones, G. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.04.25.061887 · Cited by 15 · see citing works
Circadian Mechanisms in Medicine
Lin, H. Y.-H., Yang, M.-Y., & Lin, S.-F. (2021) · New England Journal of Medicine · doi:10.1056/nejmc2104154 · Cited by 19 · see citing works
Pharmacological interventions targeting α-synuclein aggregation triggered REM sleep behavior disorder and early development of Parkinson's disease
Du, L., He, X., Fan, X., Wei, X., Xu, L., Liang, T., Wang, C., Ke, Y., & Yung, W. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108498 · Cited by 14 · see citing works
Discovery and first-time disclosure of CVN766, an exquisitely selective orexin 1 receptor antagonist
Glen, A., Bürli, R. W., Livermore, D. G., Buffham, W. J., Merison, S., Rowland, A., Newman, R., Fieldhouse, C., Miller, D. J., Dawson, L. A., et al. (2024) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2024.129629 · Cited by 13 · see citing works
The dual orexin receptor antagonist almorexant blocks the sleep-disrupting and daytime stimulant effects of methamphetamine in rhesus monkeys
Berro, L. F., Moreira-Junior, E. D. C., & Rowlett, J. K. (2021) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2021.108930 · Cited by 12 · see citing works
Residual effects of low dose of suvorexant, zolpidem, and ramelteon in healthy elderly subjects: A randomized double‐blind study
Uemura, S. I., Imanishi, A., Terui, Y., Park, I., Satake, M., Han, G., Shioya, T., Kanbayashi, T., & Nishino, S. (2022) · Neuropsychopharmacology Reports · doi:10.1002/npr2.12262 · Cited by 12 · see citing works
CYP450-Mediated metabolism of suvorexant and investigation of metabolites in forensic case specimens
Skillman, B. N., & Kerrigan, S. (2020) · Forensic Science International · doi:10.1016/j.forsciint.2020.110307 · Cited by 11 · see citing works
A Comprehensive Review of Lemborexant to Treat Insomnia
Fuller, M. C., Carlson, S. F., Grant, C., Berry, V., Ivancich, M. S., Cornett, E. M., Kaye, A. M., Viswanath, O., Urits, I., Shekoohi, S., et al. (2025) · Psychopharmacology Bulletin · doi:10.64719/pb.4483 · Cited by 11 · see citing works
Preclinical pharmacological profiles of vornorexant, a novel potent dual orexin receptor antagonist
Hikichi, H., Tokumaru, Y., Taruta, A., Konno, Y., Karasawa, J.-I., Fukumoto, K., Marumo, T., Fujii, Y., Takahashi, T., Yoshimizu, T., et al. (2025) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/j.jpet.2025.103624 · Cited by 11 · see citing works
Essential structure of orexin 1 receptor antagonist YNT-707, part III: Role of the 14-hydroxy and the 3-methoxy groups in antagonistic activity toward the orexin 1 receptor in YNT-707 derivatives lacking the 4,5-epoxy ring
Yamamoto, N., Ohrui, S., Okada, T., Saitoh, T., Kutsumura, N., Nagumo, Y., Irukayama‐Tomobe, Y., Ogawa, Y., Ishikawa, Y., Watanabe, Y., et al. (2019) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2019.03.010 · Cited by 11 · see citing works
Effect of Gabapentin on Sleep and Event‐Related Oscillations (EROs) in Rats Exposed to Chronic Intermittent Ethanol Vapor and Protracted Withdrawal
Sánchez-Alavez, M., Wills, D. N., Amodeo, L. R., & Ehlers, C. L. (2017) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.13588 · Cited by 10 · see citing works
Dual orexin receptor blocker suvorexant attenuates hypercapnic ventilatory augmentation in mice
Fukushi, I., Yokota, S., Takeda, K., Terada, J., Umeda, A., Yoshizawa, M., Kono, Y., Hasebe, Y., Onimaru, H., Pokorski, M., et al. (2022) · Brain Research · doi:10.1016/j.brainres.2022.148061 · Cited by 11 · see citing works
Pivotal role of orexin signaling in the posterior paraventricular nucleus of the thalamus during the stress-induced reinstatement of oxycodone-seeking behavior
Illenberger, J. M., Flores‐Ramirez, F. J., Pascasio, G., Franco, M., Mendonsa, B., & Martin‐Fardon, R. (2024) · Journal of Psychopharmacology · doi:10.1177/02698811241260989 · Cited by 9 · see citing works
Construction of five- and seven-membered rings facilitated by alkyne–azide functionality: access to quinoline fused triazolo-azepines
Kumar, V. B., Panchal, J. R., Sharma, V., Sharma, S., Sharma, P., & Singh, V. (2024) · Organic & Biomolecular Chemistry · doi:10.1039/d4ob01442a · Cited by 9 · see citing works
The Dual Orexin Receptor Antagonist DORA-22 Improves Mild Stress-induced Sleep Disruption During the Natural Sleep Phase of Nocturnal Rats
Gamble, M. C., Katsuki, F., McCoy, J. G., Strecker, R. E., & McKenna, J. T. (2021) · Neuroscience · doi:10.1016/j.neuroscience.2021.03.003 · Cited by 9 · see citing works
Design and synthesis of novel orexin 2 receptor agonists based on naphthalene skeleton
Hino, T., Saitoh, T., Nagumo, Y., Yamamoto, N., Kutsumura, N., Irukayama‐Tomobe, Y., Ishikawa, Y., Tanimura, R., Yanagisawa, M., & Nagase, H. (2021) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2022.128530 · Cited by 9 · see citing works
From orexin receptor agonist YNT-185 to novel antagonists with drug-like properties for the treatment of insomnia
Mezeiová, E., Janočková, J., Konecny, J., Kobrlová, T., Benková, M., Doležal, R., Prchal, L., Karasova-Zdarova, J., Soukup, O., & Korábečný, J. (2020) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2020.104179 · Cited by 9 · see citing works
Emerging medications and pharmacological treatment approaches for substance use disorders
Raymond, J. S., Athanasopoulos, A. G., Badolato, C. J., Doolan, T. M., Scicluna, R. L., Everett, N. A., Bowen, M. T., & James, M. H. (2024) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2024.173952 · Cited by 8 · see citing works
The association between serum orexin A and short‐term neurological improvement in patients with mild to moderate acute ischemic stroke
Hu, S., Ren, L., Wang, Y., Lei, Z., Cai, J., & Pan, S. (2022) · Brain and Behavior · doi:10.1002/brb3.2845 · Cited by 8 · see citing works
Pharmacokinetics, Pharmacodynamic, Safety and Tolerability of Fazamorexant, a Novel Dual Orexin Receptor Antagonist: Report of the First-in-Human Study
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Authors: Coleman, P. J., Gotter, A. L., Herring, W. J., Winrow, C. J., & Renger, J. J.
Affiliations: Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486
Department of Clinical Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486
ORCID: Coleman, Paul J.
Gotter, Anthony L.
Herring, W. Joseph
Winrow, Christopher J.
Renger, John J.
Venue: Annual Review of Pharmacology and Toxicology
Publisher: Annual Reviews
Published: 2017-01-06
Volume: 57
Issue: 1
Pages: 509-533
ISSN: 0362-1642 (ISSN-L)
1545-4304
DOI: 10.1146/annurev-pharmtox-010716-104837
OpenAlex: W2492327128
Cited by: 128
References: 143
Citations by year: 2026: 5 · 2025: 11 · 2024: 18 · 2023: 9 · 2022: 20 · 2021: 13 · 2020: 13 · 2019: 21 · 2018: 9 · 2017: 8
FWCI: 1.33
Type: journal article
Language: en
Open access: closed
Locations: The Annual Review of Pharmacology and Toxicology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
Keywords: suvorexant, orexin receptor antagonists, insomnia, dual orexin receptor antagonists, orexin signaling, narcolepsy, GABA-A receptor agonists, sleep onset, REM sleep, pharmacokinetics, cognitive performance, wakefulness
MeSH terms: Sleep Aids, Pharmaceutical, Orexin Receptor Antagonists, Animals, Azepines, Humans, Sleep Initiation and Maintenance Disorders, Triazoles, Protein Structure, Secondary, Drug Discovery, Orexin Receptors

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The discovery of suvorexant, the first orexin receptor drug for insomnia

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