ABSTRACT
The discovery of a series of 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles, dual acting norepinephrine reuptake inhibitors (NRIs) and 5-HT(2A) receptor antagonists, is described. The synthesis and structure-activity relationship (SAR) of this novel series of compounds is also presented.
Subject(s)
Indoles/pharmacology , Neurotransmitter Uptake Inhibitors/chemical synthesis , Neurotransmitter Uptake Inhibitors/pharmacology , Norepinephrine/metabolism , Serotonin 5-HT2 Receptor Antagonists , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Biological Transport/drug effects , Cell Line , Humans , Indoles/chemical synthesis , Indoles/metabolism , Neurotransmitter Uptake Inhibitors/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Serotonin Antagonists/metabolism , Structure-Activity RelationshipABSTRACT
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.
