Abstract
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 that orexin receptor agonists, especially OX2R agonist, will be useful for mechanistic therapy of the sleep disorder narcolepsy/cataplexy. We herein report the discovery of a potent (EC50 on OX2R is 0.023 μM) and OX2R-selective (OX1R/OX2R EC50 ratio is 70) agonist, 4'-methoxy-N,N-dimethyl-3'-[N-(3-{[2-(3-methylbenzamido)ethyl]amino}phenyl)sulfamoyl]-(1,1'-biphenyl)-3-carboxamide 26.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzamides / chemical synthesis*
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Benzamides / pharmacology*
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CHO Cells
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Calcium / metabolism
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Cataplexy / drug therapy
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Cell Line, Tumor
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Cricetinae
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Cricetulus
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Drug Design
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High-Throughput Screening Assays
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Humans
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Hydrogen Bonding
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Models, Molecular
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Narcolepsy / drug therapy
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Orexin Receptors / agonists*
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Small Molecule Libraries
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / pharmacology*
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X-Ray Diffraction
Substances
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4'-methoxy-N,N-dimethyl-3'-(N-(3-((2-(3-methylbenzamido)ethyl)amino)phenyl)sulfamoyl)-(1,1'-biphenyl)-3-carboxamide
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Benzamides
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Orexin Receptors
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Small Molecule Libraries
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Sulfonamides
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Calcium