Abstract
The SAR of a series of 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols as monoamine reuptake inhibitors, with a goal to improve both potency toward inhibiting the norepinephrine transporter and selectivity over the serotonin transporter, is reported. The effect of specific substitution on both the 3-phenyl group and the indole moiety were explored. This study led to the discovery of compound 20 which inhibited the norepinephrine transporter with an IC50 value of 4 nM while exhibiting 86-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 / pharmacokinetics
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Animals
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Humans
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Indoles / chemical synthesis
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Indoles / chemistry*
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Indoles / pharmacokinetics
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Models, Animal
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Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors*
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Norepinephrine Plasma Membrane Transport Proteins / metabolism
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Rats
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Selective Serotonin Reuptake Inhibitors / chemical synthesis
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Selective Serotonin Reuptake Inhibitors / chemistry
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Selective Serotonin Reuptake Inhibitors / pharmacokinetics
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Serotonin Plasma Membrane Transport Proteins / chemistry
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Serotonin Plasma Membrane Transport Proteins / metabolism
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Adrenergic Uptake Inhibitors
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Indoles
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Norepinephrine Plasma Membrane Transport Proteins
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Serotonin Plasma Membrane Transport Proteins
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Serotonin Uptake Inhibitors