Synthesis and characterization of a series of diarylguanidines that are noncompetitive N-methyl-D-aspartate receptor antagonists with neuroprotective properties

Proc Natl Acad Sci U S A. 1989 Jul;86(14):5631-5. doi: 10.1073/pnas.86.14.5631.


Four diarylguanidine derivatives were synthesized. These compounds were found to displace, at submicromolar concentrations, 3H-labeled 1-[1-(2-thienyl)cyclohexyl]piperidine and (+)-[3H]MK-801 from phencyclidine receptors in brain membrane preparations. In electrophysiological experiments the diarylguanidines blocked N-methyl-D-aspartate (NMDA)-activated ion channels. These diarylguanidines also protected rat hippocampal neurons in vitro from glutamate-induced cell death. Our results show that some diarylguanidines are noncompetitive antagonists of NMDA receptor-mediated responses and have the neuroprotective property that is commonly associated with blockers of the NMDA receptor-gated cation channel. Diarylguanidines are structurally unrelated to known blockers of NMDA channels and, therefore, represent a new compound series for the development of neuroprotective agents with therapeutic value in patients suffering from stroke, from brain or spinal cord trauma, from hypoglycemia, and possibly from brain ischemia due to heart attack.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding, Competitive
  • Brain / metabolism
  • Cell Membrane / physiology
  • Cell Survival / drug effects
  • Cells, Cultured
  • Guanidines / chemical synthesis*
  • Guanidines / pharmacology
  • Guinea Pigs
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / physiology*
  • Indicators and Reagents
  • Kinetics
  • Rats
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Neurotransmitter / drug effects*
  • Receptors, Neurotransmitter / metabolism
  • Receptors, Phencyclidine
  • Structure-Activity Relationship


  • Guanidines
  • Indicators and Reagents
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Neurotransmitter
  • Receptors, Phencyclidine