Abstract
A series of indolebutylamine derivatives were designed, synthesized, and evaluated as a novel class of selective ligands for the dopamine 3 receptor. The most potent compound 11q binds to dopamine 3 receptor with a Ki value of 124 nm and displays excellent selectivity over the dopamine 1 receptor and dopamine 2 receptor. Investigation based on structural information indicates that site S182 located in extracellular loop 2 may account for high selectivity of compounds. Interaction models of the dopamine 3 receptor-11q complex and structure-activity relationships were discussed by integrating all available experimental and computational data with the eventual aim to discover potent and selective ligands to dopamine 3 receptor.
Keywords:
dopamine 3 receptor; indolebutylamine; pharmacophore model; selectivity; structure-activity relationship.
© 2013 John Wiley & Sons A/S.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetanilides / chemical synthesis*
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Acetanilides / chemistry
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Acetanilides / metabolism
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Amino Acid Sequence
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Binding Sites
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Butylamines / chemical synthesis
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Butylamines / chemistry*
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Butylamines / metabolism
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Catalytic Domain
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Dopamine Antagonists / chemical synthesis*
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Dopamine Antagonists / chemistry
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Dopamine Antagonists / metabolism
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Dopamine D2 Receptor Antagonists
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Drug Design*
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HEK293 Cells
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Humans
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Indoles / chemical synthesis*
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Indoles / chemistry*
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Indoles / metabolism
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Ligands
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Molecular Docking Simulation
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Molecular Sequence Data
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Protein Binding
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Receptors, Dopamine D1 / antagonists & inhibitors
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Receptors, Dopamine D1 / genetics
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Receptors, Dopamine D1 / metabolism
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Receptors, Dopamine D2 / genetics
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Receptors, Dopamine D2 / metabolism
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Receptors, Dopamine D3 / antagonists & inhibitors*
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Receptors, Dopamine D3 / genetics
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Receptors, Dopamine D3 / metabolism
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Structure-Activity Relationship
Substances
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Acetanilides
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Butylamines
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Dopamine Antagonists
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Dopamine D2 Receptor Antagonists
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Indoles
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Ligands
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N-cyclohexyl-2-(4-(4-(5-fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)-N-(2-methoxyphenyl)acetamide
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Receptors, Dopamine D1
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Receptors, Dopamine D2
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Receptors, Dopamine D3
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indole