Abstract
A series of N'-[3-(indole-1-sulfonyl) aryl]-N,N-dimethyl ethane-1,2-diamines and N'-[3-(indole-1-sulfonyl) aryl]-N,N-dimethyl propane-1,3-diamines was designed and synthesized as 5-HT6 receptor ligands. These compounds, when screened in a functional reporter gene-based assay, displayed potent antagonistic activity with Kb values in the range of 1.8-60 nM. The lead compound 9y has shown good ADME surrogate properties, acceptable pharmacokinetic profile and is active in animal models of cognition like novel object recognition test and Morris water maze. It was selected for detailed profiling.
Keywords:
5-Hydroxytryptamine6 receptor; central nervous system; cognition; novel object recognition test; structure activity relationship; water maze.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amines / chemical synthesis
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Amines / pharmacokinetics
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Amines / pharmacology*
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Animals
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / metabolism*
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CHO Cells
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Cricetulus
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Exploratory Behavior / drug effects
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Exploratory Behavior / physiology
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Gene Expression
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Genes, Reporter
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Humans
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Indoles / chemical synthesis
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Indoles / pharmacokinetics
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Indoles / pharmacology*
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Kinetics
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Ligands
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Luciferases / genetics
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Luciferases / metabolism
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Male
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Maze Learning / drug effects
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Maze Learning / physiology
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Rats
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Rats, Wistar
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Receptors, Serotonin / genetics
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Receptors, Serotonin / metabolism*
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Serotonin Antagonists / chemical synthesis
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Serotonin Antagonists / pharmacokinetics
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Serotonin Antagonists / pharmacology*
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology*
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Swimming
Substances
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Amines
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Indoles
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Ligands
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Receptors, Serotonin
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Recombinant Proteins
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Serotonin Antagonists
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Sulfonamides
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serotonin 6 receptor
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Luciferases