Structure-Activity Relationship, Pharmacological Characterization, and Molecular Modeling of Noncompetitive Inhibitors of the Betaine/γ-Aminobutyric Acid Transporter 1 (BGT1)

Author(s)
Lars Jorgensen, Anas Al-Khawaja, Stefanie Kickinger, Stine B. Vogensen, Jonas Skovgaard-Petersen, Emil Rosenthal, Nrupa Borkar, Rebekka Loffler, Karsten K. Madsen, Hans Brauner-Osbome, Arne Schousboe, Gerhard F. Ecker, Petrine Wellendorph, Rasmus P. Causen
Abstract

N-(1-Benzyl-4-piperidinyl)-2,4-dichlorobenzamide 5 (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 26m as a more soluble 2,4-Cl substituted 3-pyridine analogue with retained BGT1 activity and an improved off-target profile compared to 5. 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.

Organisation(s)
Department of Pharmaceutical Chemistry
External organisation(s)
University of Copenhagen
Journal
Journal of Medicinal Chemistry
Volume
60
Pages
8834-8846
No. of pages
13
ISSN
0022-2623
DOI
https://doi.org/10.1021/acs.jmedchem.7b00924
Publication date
11-2017
Peer reviewed
Yes
Austrian Fields of Science 2012
Pharmaceutical chemistry
Keywords
Portal url
https://ucris.univie.ac.at/portal/en/publications/structureactivity-relationship-pharmacological-characterization-and-molecular-modeling-of-noncompetitive-inhibitors-of-the-betaineaminobutyric-acid-transporter-1-bgt1(c896679d-a536-4e9c-9bd5-e282cda66bb2).html