Recent Advances and Challenges of the Drugs Acting on Monoamine Transporters

Curr Med Chem. 2020;27(23):3830-3876. doi: 10.2174/0929867325666181009123218.


Background: The human Monoamine Transporters (hMATs), primarily including hSERT, hNET and hDAT, are important targets for the treatment of depression and other behavioral disorders with more than the availability of 30 approved drugs.

Objective: This paper is to review the recent progress in the binding mode and inhibitory mechanism of hMATs inhibitors with the central or allosteric binding sites, for the benefit of future hMATs inhibitor design and discovery. The Structure-Activity Relationship (SAR) and the selectivity for hit/lead compounds to hMATs that are evaluated by in vitro and in vivo experiments will be highlighted.

Methods: PubMed and Web of Science databases were searched for protein-ligand interaction, novel inhibitors design and synthesis studies related to hMATs.

Results: Literature data indicate that since the first crystal structure determinations of the homologous bacterial Leucine Transporter (LeuT) complexed with clomipramine, a sizable database of over 100 experimental structures or computational models has been accumulated that now defines a substantial degree of structural variability hMATs-ligands recognition. In the meanwhile, a number of novel hMATs inhibitors have been discovered by medicinal chemistry with significant help from computational models.

Conclusion: The reported new compounds act on hMATs as well as the structures of the transporters complexed with diverse ligands by either experiment or computational modeling have shed light on the poly-pharmacology, multimodal and allosteric regulation of the drugs to transporters. All of the studies will greatly promote the Structure-Based Drug Design (SBDD) of structurally novel scaffolds with high activity and selectivity for hMATs.

Keywords: Monoamine transporters; allosteric modulation; common binding mode; computational modeling; drug selectivity; multi-target drug; structure activity analysis..

Publication types

  • Review

MeSH terms

  • Binding Sites
  • Humans
  • Ligands
  • Norepinephrine Plasma Membrane Transport Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Structure-Activity Relationship*


  • Ligands
  • Norepinephrine Plasma Membrane Transport Proteins
  • Serotonin Plasma Membrane Transport Proteins