Bolshakov K V, Kim K H, Potapjeva N N, Gmiro V E, Tikhonov D B, Usherwood P N R, Mellor I R, Magazanik L G
Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, St. Petersburg, Russia.
Neuropharmacology. 2005 Aug;49(2):144-55. doi: 10.1016/j.neuropharm.2005.02.007.
Determinants of antagonism of NMDA and calcium permeable AMPA receptor channels by organic cations were studied using several homologous series of mono- and dicationic derivatives of adamantane, phenylcyclohexyl, triphenylmethane, diphenylmethane. Antagonism by these drugs was studied on native receptors of isolated rat brain neurons and on recombinant GluR1 receptors expressed by Xenopus oocytes. The major action of these compounds was on the open channel, although minor competitive or closed channel antagonism cannot be ruled out. Analysis of structure-activity relationships suggests that all organic monocations are selective antagonists of NMDA receptors. Compounds exhibiting trapping block are more potent than those exhibiting weakly-trapping block. AMPA and NMDA receptor channels are blocked by dicationic organic compounds, the former requiring a certain distance between the hydrophobic moiety and the terminal charged group. Variations of their terminal ammonium group demonstrated that trimethylammonium derivatives are the most potent antagonists of AMPA receptors, whereas the terminal amino group is optimal for block of NMDA receptors. Based on the action of 38 compounds, topographical models of the binding sites of these compounds on NMDA and AMPA receptor channels are presented. These models will help to design channel-blocking drugs with defined potency and selectivity of action.
利用金刚烷、苯基环己基、三苯甲烷、二苯甲烷的几个同系单阳离子和双阳离子衍生物系列，研究了有机阳离子对NMDA和钙通透性AMPA受体通道的拮抗作用的决定因素。在分离的大鼠脑神经元的天然受体和非洲爪蟾卵母细胞表达的重组GluR1受体上研究了这些药物的拮抗作用。这些化合物的主要作用是作用于开放通道，尽管不能排除轻微的竞争性或封闭通道拮抗作用。构效关系分析表明，所有有机单阳离子都是NMDA受体的选择性拮抗剂。表现出捕获阻断的化合物比表现出弱捕获阻断的化合物更有效。AMPA和NMDA受体通道被双阳离子有机化合物阻断，前者要求疏水部分和末端带电基团之间有一定距离。其末端铵基团的变化表明，三甲基铵衍生物是AMPA受体最有效的拮抗剂，而末端氨基对于阻断NMDA受体是最佳的。基于38种化合物的作用，给出了这些化合物在NMDA和AMPA受体通道上结合位点的拓扑模型。这些模型将有助于设计具有确定效力和作用选择性的通道阻断药物。
