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

J Med Chem. 2017 Nov 9;60(21):8834-8846. doi: 10.1021/acs.jmedchem.7b00924. Epub 2017 Oct 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Benzamides / pharmacology
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / genetics
  • Chimera
  • GABA Plasma Membrane Transport Proteins / genetics
  • GABA Uptake Inhibitors / chemistry*
  • Humans
  • Models, Molecular
  • Piperidines / pharmacology
  • Serotonin Plasma Membrane Transport Proteins / chemistry
  • Structure-Activity Relationship

Substances

  • Benzamides
  • Carrier Proteins
  • GABA Plasma Membrane Transport Proteins
  • GABA Uptake Inhibitors
  • N-(1-benzyl-4-piperidinyl)-2,4-dichlorobenzamide
  • Piperidines
  • SLC6A11 protein, human
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • betaine plasma membrane transport proteins