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

作者：John F. W. Keana, Robert N McBurney, Michael W. Scherz, James B. Fischer, Pauline Hamilton, Stephen M. Smith, Alfred C. Server, Steven M. Finkbeiner, Charles F. Stevens, Craig E. Jahr · 发表于：Proceedings of the National Academy of Sciences · 年份：1989 · DOI：10.1073/pnas.86.14.5631 · 被引用次数：47 · 研究领域：Neuroscience and Neuropharmacology Research、Ion channel regulation and function、Pharmacological Receptor Mechanisms and Effects

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.