Keana J F, McBurney R N, Scherz M W, Fischer J B, Hamilton P N, Smith S M, Server A C, Finkbeiner S, Stevens C F, Jahr C
Department of Chemistry, University of Oregon, Eugene 97403.
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.
合成了四种二芳基胍衍生物。发现这些化合物在亚微摩尔浓度下能从脑膜制剂中的苯环利定受体上取代3H标记的1-[1-(2-噻吩基)环己基]哌啶和(+)-[3H]MK-801。在电生理实验中，二芳基胍阻断了N-甲基-D-天冬氨酸(NMDA)激活的离子通道。这些二芳基胍还能在体外保护大鼠海马神经元免受谷氨酸诱导的细胞死亡。我们的结果表明，一些二芳基胍是NMDA受体介导反应的非竞争性拮抗剂，具有通常与NMDA受体门控阳离子通道阻滞剂相关的神经保护特性。二芳基胍在结构上与已知的NMDA通道阻滞剂无关，因此，代表了一个新的化合物系列，可用于开发对中风、脑或脊髓创伤、低血糖以及可能因心脏病发作导致的脑缺血患者具有治疗价值的神经保护剂。
