Design, synthesis and biological evaluation of 1-benzyl-5-oxopyrrolidine-2-carboximidamide derivatives as novel neuroprotective agents

Eur J Med Chem. 2019 Nov 15:182:111654. doi: 10.1016/j.ejmech.2019.111654. Epub 2019 Aug 28.

Abstract

A series of 1-benzyl-5-oxopyrrolidine-2-carboximidamide derivatives were designed and synthesized. Their protective activities against N-methyl-d-aspartic acid (NMDA)-induced cytotoxicity were investigated in vitro. All of the compounds exhibited neuroprotective activities, especially 12k, which showed higher potency than reference compound 1 (ifenprodil). Further investigation showed that 12k could attenuate Ca2+ influx and suppress the NR2B upregulation induced by NMDA. The docking results indicated that 12k could fit well into binding site of 1 in the NR2B-NMDA receptor. Additionally, 12k exhibited excellent metabolic stability. Furthermore, the results of behavioral tests showed that compound 12k could significantly improve learning and memory in vivo. These results suggested that 12k is a promising neuroprotective drug candidate and that the NR2B-NMDA receptor is a potential target of 12k.

Keywords: Behavioral tests; Ca(2+) influx; NMDA; NR2B-NMDA receptor; Neuroprotective activity.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Male
  • Maze Learning / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Molecular Structure
  • N-Methylaspartate / antagonists & inhibitors
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Neuroprotective Agents
  • Pyrrolidines
  • N-Methylaspartate
  • pyrrolidine