Abstract
A novel series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the (2R,3S)-isomer to be a potent norepinephrine reuptake inhibitor (IC(50)=28 nM) with excellent selectivity over the dopamine transporter and 13-fold selectivity over the serotonin transporter.
MeSH terms
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Adrenergic Uptake Inhibitors / chemical synthesis
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Adrenergic Uptake Inhibitors / chemistry*
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Adrenergic Uptake Inhibitors / pharmacology
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Animals
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Antidepressive Agents / chemical synthesis
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Antidepressive Agents / chemistry*
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Antidepressive Agents / pharmacology
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CHO Cells
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Cell Line
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Cricetinae
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Cricetulus
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Crystallography, X-Ray
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Dogs
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Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors
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Dopamine Plasma Membrane Transport Proteins / metabolism
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Drug Discovery
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Humans
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Molecular Conformation
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Norepinephrine / antagonists & inhibitors*
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Propanols / chemical synthesis
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Propanols / chemistry*
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Propanols / pharmacology
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Serotonin Plasma Membrane Transport Proteins / metabolism
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Structure-Activity Relationship
Substances
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Adrenergic Uptake Inhibitors
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Antidepressive Agents
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Dopamine Plasma Membrane Transport Proteins
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Propanols
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Recombinant Proteins
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Serotonin Plasma Membrane Transport Proteins
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Norepinephrine