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Abstract: Orexins/hypocretins are key neuropeptides responsible for regulating central arousal and reward circuits. Two receptors respond to orexin signaling, orexin 1 receptor (OX(1)R) and orexin 2 receptor (OX(2)R) with partially overlapping nervous system distributions. Genetic studies suggest orexin receptor antagonists could be therapeutic for insomnia and other disorders with disruptions of sleep and wake. Suvorexant (MK-4305) is a potent, selective, and orally bioavailable antagonist of OX(1)R and OX(2)R currently under clinical investigation as a novel therapy for insomnia. Examination of Suvorexant in radioligand binding assays using tissue from transgenic rats expressing the human OX(2)R found nearly full receptor occupancy (>90%) at plasma exposures of 1.1 μM. Dosed orally Suvorexant significantly and dose-dependently reduced locomotor activity and promoted sleep in rats (10, 30, and 100 mg/kg), dogs (1 and 3 mg/kg), and rhesus monkeys (10 mg/kg). Consistent cross-species sleep/wake architecture changes produced by Suvorexant highlight a unique opportunity to develop dual orexin antagonists as a novel therapy for insomnia.
Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania, USA.
This article was published in the following journal.
Name: Journal of neurogenetics
Orexins are a family of neuropeptides that regulate sleep/wakefulness, acting on two G protein-coupled receptors, orexin receptors-1 (OX1R) and -2 (OX2R). Genetic and pharmacologic evidence suggests t...
In this issue, Nagase and colleagues report the discovery of the first selective nonpeptidic orexin 2 receptor (OX2R) agonists. The discovery of these OX2R selective agonists opens up new avenues for ...
Although intrathecal orexin-A has been known to be antinociceptive in various pain models, the role of orexin-A in antinociception is not well characterized. In the present study, we examined whether ...
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To evaluate next-morning driving performance in adults younger than 65 years, after single and repeated doses of suvorexant 20 and 40 mg.
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The purpose of this study is to assess the effects of daily administration of rabeprazole on the single-dose pharmacokinetics of JNJ-42847922 in healthy participants.
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Periods of sleep manifested by changes in EEG activity and certain behavioral correlates; includes Stage 1: sleep onset, drowsy sleep; Stage 2: light sleep; Stages 3 and 4: delta sleep, light sleep, deep sleep, telencephalic sleep.
Dyssomnias (i.e., insomnias or hypersomnias) associated with dysfunction of internal sleep mechanisms or secondary to a sleep-related medical disorder (e.g., sleep apnea, post-traumatic sleep disorders, etc.). (From Thorpy, Sleep Disorders Medicine, 1994, p187)
Movements or behaviors associated with sleep, sleep stages, or partial arousals from sleep that may impair sleep maintenance. Parasomnias are generally divided into four groups: arousal disorders, sleep-wake transition disorders, parasomnias of REM sleep, and nonspecific parasomnias. (From Thorpy, Sleep Disorders Medicine, 1994, p191)
A sleep disorder of central nervous system origin characterized by prolonged nocturnal sleep and periods of daytime drowsiness. Affected individuals experience difficulty with awakening in the morning and may have associated sleep drunkenness, automatic behaviors, and memory disturbances. This condition differs from narcolepsy in that daytime sleep periods are longer, there is no association with CATAPLEXY, and the multiple sleep latency onset test does not record sleep-onset rapid eye movement sleep. (From Chokroverty, Sleep Disorders Medicine, 1994, pp319-20; Psychiatry Clin Neurosci 1998 Apr:52(2):125-129)
Conditions characterized by disturbances of usual sleep patterns or behaviors. Sleep disorders may be divided into three major categories: DYSSOMNIAS (i.e. disorders characterized by insomnia or hypersomnia), PARASOMNIAS (abnormal sleep behaviors), and sleep disorders secondary to medical or psychiatric disorders. (From Thorpy, Sleep Disorders Medicine, 1994, p187)
Sleep disorders disrupt sleep during the night, or cause sleepiness during the day, caused by physiological or psychological factors. The common ones include snoring and sleep apnea, insomnia, parasomnias, sleep paralysis, restless legs syndrome, circa...
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