Abstract
A series of potential new 5-HT2 receptor scaffolds based on a simplification of the clinically studied, 5-HT2CR agonist vabicaserin, were designed. An in vivo feeding assay early in our screening process played an instrumental part in the lead identification process, leading us to focus on a 6,5,7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT2C receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.
Keywords:
5-HT(2C) receptor; Agonist; GPCR; Lead identification.
Copyright © 2019. Published by Elsevier Ltd.
MeSH terms
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Animals
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Benzodiazepines / chemical synthesis
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Benzodiazepines / metabolism
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Benzodiazepines / pharmacokinetics
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Benzodiazepines / pharmacology*
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Dogs
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Drug Discovery
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Drug Stability
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Heterocyclic Compounds, 3-Ring / chemical synthesis
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Heterocyclic Compounds, 3-Ring / metabolism
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Heterocyclic Compounds, 3-Ring / pharmacokinetics
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Heterocyclic Compounds, 3-Ring / pharmacology*
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Humans
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Macaca fascicularis
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Male
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Mice
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Microsomes / metabolism
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Molecular Structure
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Rats, Sprague-Dawley
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Receptor, Serotonin, 5-HT2C / metabolism*
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Serotonin 5-HT2 Receptor Agonists / chemical synthesis
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Serotonin 5-HT2 Receptor Agonists / metabolism
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Serotonin 5-HT2 Receptor Agonists / pharmacokinetics
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Serotonin 5-HT2 Receptor Agonists / pharmacology*
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Structure-Activity Relationship
Substances
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Heterocyclic Compounds, 3-Ring
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Receptor, Serotonin, 5-HT2C
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Serotonin 5-HT2 Receptor Agonists
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Benzodiazepines