Abstract
Orexins are excitatory neuropeptides that have a critical role in maintaining wakefulness. Orexin receptor antagonists promote sleep in animals and humans. Indeed, small molecule orexin receptor antagonists have demonstrated clinical proof-of-concept in the treatment of primary insomnia. This review describes optimization of orexin receptor antagonists across diverse structural classes with a focus on how molecules were designed to optimize potency, physicochemical properties, pharmacokinetics, brain penetration, and in vivo activity.
MeSH terms
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Animals
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Drug Discovery*
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Humans
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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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Orexin Receptors
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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 Initiation and Maintenance Disorders / drug therapy*
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Sleep Initiation and Maintenance Disorders / metabolism
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Spiro Compounds / chemical synthesis
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacokinetics
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Spiro Compounds / pharmacology
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Structure-Activity Relationship
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Tetrahydroisoquinolines / chemical synthesis
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Tetrahydroisoquinolines / chemistry
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Tetrahydroisoquinolines / pharmacokinetics
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Tetrahydroisoquinolines / pharmacology
Substances
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Indoles
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Orexin Receptors
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Receptors, G-Protein-Coupled
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Receptors, Neuropeptide
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Spiro Compounds
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Tetrahydroisoquinolines