Aminotriazines with indole motif as novel, 5-HT7 receptor ligands with atypical binding mode

Bioorg Chem. 2020 Nov:104:104254. doi: 10.1016/j.bioorg.2020.104254. Epub 2020 Sep 2.

Abstract

Developing new and selective 5-HT7R ligands may have a key impact on the treatment of central nervous system diseases including depression. We have found that indoleaminotriazine core fused with alkyl aryl moiety exhibits high affinity and selectivity to 5-HT7R. SAR analysis demonstrated that the ethyl or ethoxy group (5c 5-HT7R Ki = 8 nM; 5d 5-HT7R Ki = 55 nM) is the optimal carbon linker between triazine and aryl moiety. The results of the molecular dynamics simulations show stable interaction with E7.34 upon binding to a 5-HT7R. Compounds 5c and 5d were tested for early ADMET parameters. Compounds are not hepatotoxic and exhibit moderate potential interaction with other drugs metabolized by CYP3A4 or CYP2D6.

Keywords: 5-HT(7)R ligands; Docking; Drug design; Medicinal chemistry; Microwave chemistry; Molecular dynamics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / drug effects
  • Dose-Response Relationship, Drug
  • Hep G2 Cells
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Receptors, Serotonin / metabolism*
  • Serotonin Antagonists / chemical synthesis
  • Serotonin Antagonists / chemistry
  • Serotonin Antagonists / pharmacology*
  • Serotonin Receptor Agonists / chemical synthesis
  • Serotonin Receptor Agonists / chemistry
  • Serotonin Receptor Agonists / pharmacology*
  • Structure-Activity Relationship
  • Triazines / chemistry
  • Triazines / pharmacology*

Substances

  • Indoles
  • Ligands
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Triazines
  • serotonin 7 receptor
  • indole