1 research outputs found
Structure–Activity Relationship, Pharmacological Characterization, and Molecular Modeling of Noncompetitive Inhibitors of the Betaine/γ-Aminobutyric Acid Transporter 1 (BGT1)
<i>N</i>-(1-Benzyl-4-piperidinyl)-2,4-dichlorobenzamide <b>5</b> (BPDBA) is a noncompetitive inhibitor of the betaine/GABA
transporter 1 (BGT1). We here report the synthesis and structure–activity
relationship of 71 analogues. We identify <b>26m</b> as a more
soluble 2,4-Cl substituted 3-pyridine analogue with retained BGT1
activity and an improved off-target profile compared to <b>5</b>. We performed radioligand-based uptake studies at chimeric constructs
between BGT1 and GAT3, experiments with site-directed mutated transporters,
and computational docking in a BGT1 homology model based on the newly
determined X-ray crystal structure of the human serotonin transporter
(hSERT). On the basis of these experiments, we propose a binding mode
involving residues within TM10 in an allosteric site in BGT1 that
corresponds to the allosteric binding pocket revealed by the hSERT
crystal structure. Our study provides first insights into a proposed
allosteric binding pocket in BGT1, which accommodates the binding
site for a series of novel noncompetitive inhibitors