Abstract
Based on a medicinal chemistry guided hypothetical pharmacophore model, novel series of indolyl sulfonamides have been designed and prepared as selective and high-affinity serotonin 5-HT(6) receptor ligands. Furthermore, based on a screening approach of a discovery library, a series of benzoxazinepiperidinyl sulfonamides were identified as selective 5-HT(6) ligands. Many of the compounds described in this paper possess excellent affinities, displaying pK(i) values greater than 8 (some even >9) and high selectivities against a wide range (>50) of other CNS relevant receptors. First, structure-affinity relationships of these ligands are discussed. In terms of functionality, high-affinity antagonists, as well as agonists and even partial agonists, were prepared. Compounds 19c and 19g represent the highest-affinity 5-HT(6) agonists ever reported in the literature. These valuable tool compounds should allow for the detailed study of the role of the 5-HT(6) receptor in relevant animal models of disorders such as cognition deficits, depression, anxiety, or obesity.
MeSH terms
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Adenylyl Cyclases / biosynthesis
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Benzoxazines / chemical synthesis
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Benzoxazines / chemistry
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Cell Line
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Humans
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Ligands
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Piperidines / chemical synthesis
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Piperidines / chemistry
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Radioligand Assay
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Receptors, Serotonin / drug effects*
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Serotonin Antagonists / chemical synthesis*
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Serotonin Antagonists / chemistry
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Serotonin Antagonists / pharmacology
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Serotonin Receptor Agonists / chemical synthesis*
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Serotonin Receptor Agonists / chemistry
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Serotonin Receptor Agonists / pharmacology
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
Substances
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Benzoxazines
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Indoles
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Ligands
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N-(3-(2-diethylaminoethyl)-1H-indol-5-yl)-5-chloro-3-methylbenzo(b)thiophene-2-sulfonamide
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N-(3-(2-dimethylaminoethyl)-1H-indol-5-yl)-5-chloro-3-methylbenzo(b)thiophene-2-sulfonamide
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N-(3-(2-dimethylaminoethyl)-1H-indol-5-yl)-5-chloronaphthalene-2-sulfonamide
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Piperidines
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Receptors, Serotonin
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Serotonin Antagonists
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Serotonin Receptor Agonists
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Sulfonamides
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serotonin 6 receptor
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Adenylyl Cyclases