Abstract
Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, 1 (SB-649868), or suvorexant have shown promise for the treatment of insomnias and sleep disorders in several recent clinical trials in volunteers and primary insomnia patients. The relative contribution of antagonism of OX1R and OX2R for sleep induction is still a matter of debate. We therefore initiated a drug discovery project with the aim of creating both OX2R selective antagonists and DORAs. Here we report that the OX2R selective antagonist 26 induced sleep in mice primarily by increasing NREM sleep, whereas the DORA suvorexant induced sleep largely by increasing REM sleep. Thus, OX2R selective antagonists may also be beneficial for the treatment of insomnia.
MeSH terms
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Animals
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Azepines / pharmacology
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Electroencephalography
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Electromyography
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Indoles / chemical synthesis
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Indoles / chemistry
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Indoles / pharmacokinetics
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Indoles / pharmacology
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Male
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Mice
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Mice, Inbred C57BL
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Motor Activity / drug effects
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Orexin Receptor Antagonists*
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Pyrimidines / chemical synthesis
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Quinoxalines / chemical synthesis
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Quinoxalines / pharmacokinetics
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Quinoxalines / pharmacology
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Sleep / drug effects*
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Sleep Initiation and Maintenance Disorders / drug therapy*
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Sleep Stages / drug effects
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Spiro Compounds / chemical synthesis*
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Spiro Compounds / pharmacokinetics
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Spiro Compounds / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Triazoles / pharmacology
Substances
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Azepines
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Indoles
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Orexin Receptor Antagonists
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Pyrimidines
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Quinoxalines
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Spiro Compounds
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Triazoles
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suvorexant