Harris E W, Ganong A H, Monaghan D T, Watkins J C, Cotman C W
Brain Res. 1986 Sep 10;382(1):174-7. doi: 10.1016/0006-8993(86)90128-9.
A new compound, 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), has been evaluated as an excitatory amino acid receptor antagonist using electrophysiological assays and radioligand binding. In autoradiographic preparations, CPP reduces L-[3H]glutamate binding in regions of the hippocampus rich in N-methyl-D-aspartate (NMDA) receptors, but not in regions rich in kainate sites. In isolated membrane fraction preparations, CPP displaces L-[3H]glutamate binding to NMDA sites, but does not compete with the binding of selective kainate or quisqualate site ligands. CPP potently reduces depolarizations produced by application of NMDA but not depolarizations produced by quisqualate or kainate. Its order of potency against excitatory amino acid-induced responses in the hippocampus is NMDA greater than homocysteate greater than aspartate greater than glutamate greater than kainate greater than or equal to quisqualate. CPP has no effect on lateral perforant path responses or on inhibition of these responses by 2-amino-4-phosphonobutyrate. Finally, at doses that do not affect Schaffer collateral synaptic transmission, CPP reversibly blocks the induction of long-term potentiation of Schaffer synaptic responses. This new compound is, therefore, a highly selective brain NMDA receptor blocker, and the most potent such by nearly an order of magnitude.
一种新的化合物，3-((±)-2-羧基哌嗪-4-基)-丙基-1-膦酸（CPP），已通过电生理测定和放射性配体结合法被评估为一种兴奋性氨基酸受体拮抗剂。在放射自显影片制备中，CPP可降低富含N-甲基-D-天冬氨酸（NMDA）受体的海马区域的L-[3H]谷氨酸结合，但在富含海人藻酸位点的区域则无此作用。在分离的膜组分制备中，CPP可取代L-[3H]谷氨酸与NMDA位点的结合，但不与选择性海人藻酸或quisqualate位点配体的结合竞争。CPP能有效降低NMDA应用所产生的去极化，但不能降低quisqualate或海人藻酸所产生的去极化。其对海马中兴奋性氨基酸诱导反应的效力顺序为：NMDA＞同型半胱氨酸＞天冬氨酸＞谷氨酸＞海人藻酸＞或等于quisqualate。CPP对侧穿通通路反应或2-氨基-4-膦酰丁酸对这些反应的抑制均无影响。最后，在不影响Schaffer侧支突触传递的剂量下，CPP可可逆性地阻断Schaffer突触反应的长时程增强的诱导。因此，这种新化合物是一种高度选择性的脑NMDA受体阻滞剂，且其效力最强，几乎比其他同类药物高一个数量级。
