Bolshakov K V, Gmiro V E, Tikhonov D B, Magazanik L G
Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, St. Petersburg, Russia.
J Neurochem. 2003 Oct;87(1):56-65. doi: 10.1046/j.1471-4159.2003.01956.x.
Open channel blockers of NMDA receptors interact with the channel gate in different ways. Compounds like MK-801 and phencyclidine exhibit pronounced trapping block, whereas 9-aminoacridine and tetrapentylammonium cannot be trapped. Some blockers such as memantine and amantadine exhibit intermediate properties, so called 'partial trapping'. To analyze the determinants of trapping we have synthesized a series of mono- and dicationic derivatives of phenylcyclohexyl. The blocking action of these compounds as well as that of amantadine has been studied on native NMDA receptors of hippocampal pyramidal neurons. Use-dependence and kinetics of the blockade have been analyzed to estimate the degree of trapping. Dimensions of the blocking molecules apparently do not correlate with their trapping. However, the degree of trapping is voltage-dependent and correlates with the kinetics of unblock. For instance, amantadine behaved as non-trapping blocker at positive voltages, but demonstrated significant trapping at negative voltages. The data may be explained by the model in which the NMDA receptor channel has two binding sites: the shallow and deep ones. Binding to the deep but not to the shallow site allows trapping of the blockers.
N-甲基-D-天冬氨酸（NMDA）受体的开放通道阻滞剂以不同方式与通道门相互作用。像MK-801和苯环己哌啶这样的化合物表现出明显的捕获性阻滞，而9-氨基吖啶和四戊基铵则不能被捕获。一些阻滞剂如美金刚和金刚烷胺表现出中间性质，即所谓的“部分捕获”。为了分析捕获的决定因素，我们合成了一系列苯基环己基的单阳离子和双阳离子衍生物。已经在海马锥体神经元的天然NMDA受体上研究了这些化合物以及金刚烷胺的阻断作用。分析了阻断的使用依赖性和动力学以估计捕获程度。阻断分子的尺寸显然与其捕获无关。然而，捕获程度是电压依赖性的，并且与解封动力学相关。例如，金刚烷胺在正电压下表现为非捕获性阻滞剂，但在负电压下表现出明显的捕获。这些数据可以用NMDA受体通道有两个结合位点的模型来解释：浅位点和深位点。与深位点而非浅位点结合允许阻滞剂被捕获。
