Synthesis and biological evaluation of new multi-target 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with potential antidepressant effect

Eur J Med Chem. 2019 Dec 1:183:111736. doi: 10.1016/j.ejmech.2019.111736. Epub 2019 Sep 26.

Abstract

A series of novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesised and evaluated for their 5-HT1A/D2/5-HT2A/5-HT6/5-HT7 receptor affinity and serotonin reuptake inhibition. Most of the evaluated compounds displayed high affinities for 5-HT1A receptors (e.g., 4cKi = 2.3 nM, 4lKi = 3.2 nM). The antidepressant activity of the selected compounds was screened in vivo using the forced swim test (FST). The results indicate that compound MW005 (agonist of the pre- and postsynaptic 5-HT1A receptor) exhibited promising affinities for the 5-HT1A/SERT/D2/5-HT6/5-HT7 receptors and showed an antidepressant-like activity in the FST model.

Keywords: 5-HT(1A) agonists; 5-HT(1A)/SERT dual activity; Antidepressants; D(2) receptor ligands; Multitarget directed ligand; Serotonin reuptake inhibitors.

MeSH terms

  • Animals
  • Antidepressive Agents* / chemical synthesis
  • Antidepressive Agents* / pharmacology
  • CHO Cells
  • Cricetulus
  • HEK293 Cells
  • Humans
  • Indoles* / chemical synthesis
  • Indoles* / pharmacology
  • Male
  • Mice
  • Pyrrolidinones* / chemical synthesis
  • Pyrrolidinones* / pharmacology
  • Receptors, Serotonin / metabolism
  • Selective Serotonin Reuptake Inhibitors / chemical synthesis
  • Selective Serotonin Reuptake Inhibitors / metabolism
  • Selective Serotonin Reuptake Inhibitors / pharmacology

Substances

  • 3-(1H-indol-3-yl)pyrrolidine-2,5-dione
  • Antidepressive Agents
  • Indoles
  • Pyrrolidinones
  • Receptors, Serotonin
  • Serotonin Uptake Inhibitors