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Inhibition mechanisms of multiple drugs on norepinephrine, dopamine, and serotonin transporters
Author(s) -
Choi KeeHyun
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb517
Subject(s) - norepinephrine transporter , monoamine neurotransmitter , serotonin , dopamine , serotonin transporter , pharmacology , neurotransmitter , chemistry , neurotransmitter transporter , dopamine transporter , transporter , reuptake inhibitor , serotonin plasma membrane transport proteins , norepinephrine , reuptake , fluoxetine , biochemistry , biology , endocrinology , receptor , gene
Monoamine transporters (norepinephrine, dopamine, and serotonin transporters (NET, DAT, and SERT, respectively)) are localized to presynaptic sites, where they terminate neurotransmitter transmission and maintain presynaptic neurotransmitter storage. Due to the essential roles of neurotransmitters in brain, monoamine transporters are important therapeutic targets. In particular, triple‐acting agents simultaneously inhibiting NET, DAT, and SERT are under clinical evaluation for treating depression. Given their therapeutic values, in the present study, pharmacological properties of NET, DAT, and SERT were investigated using selective inhibitors of each transporter (nisoxetine, vanoxerine, and fluoxetine, respectively) as well as non‐selective inhibitors. Binding affinities were measured by competitive affinity assays using radioactive ligands, while inhibitor potencies were determined by fluorescence‐based uptake assays. The IC 50 values of inhibitors in uptake assays were compared with the K d values in binding assays, revealing substantial differences between potency and binding affinity (IC 50 >;>; K d ) for SERT, but not for NET or DAT. It suggests additional critical steps other than binding might be necessary to exert inhibitory effects on SERT. Multiple drugs on individual transporter were also examined, resulting in additive effects.