Abstract
Silent Night: Antagonism of the orexin (or hypocretin) system has recently been identified as a novel mechanism for the treatment of insomnia. Herein, we describe discovery of a dual (OX(1)R/OX(2)R) orexin receptor antagonist featuring a 1,4-diazepane central constraint that blocks orexin signaling in vivo. In telemetry-implanted rats, oral administration of this antagonist produced a decrease in wakefulness, while increasing REM and non-REM sleep.
MeSH terms
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Animals
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Azepines / chemistry*
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Azepines / pharmacokinetics
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Azepines / therapeutic use
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Central Nervous System / drug effects
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Orexin Receptors
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Rats
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Receptors, G-Protein-Coupled / antagonists & inhibitors*
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Receptors, G-Protein-Coupled / metabolism
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Receptors, Neuropeptide / antagonists & inhibitors*
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Receptors, Neuropeptide / metabolism
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Sleep Wake Disorders / drug therapy*
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Structure-Activity Relationship
Substances
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Azepines
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Orexin Receptors
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Receptors, G-Protein-Coupled
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Receptors, Neuropeptide