Pharmacological implications of two distinct mechanisms of interaction of memantine with N-methyl-D-aspartate-gated channels
Pharmacological implications of two distinct mechanisms of interaction of memantine with N-methyl-D-aspartate-gated channels
复制标题
DOI：
10.1124/jpet.105.085142
复制
发表时间：
2005-09-01
影响因子：
3.5
通讯作者：
Lipton, SA
中科院分区：
文献类型：
--
作者：
Chen, HSV;Lipton, SA
与其他N-甲基-D-天冬氨酸受体(NMDAR)拮抗剂不同，临床试验表明美金刚在临床上是耐受的，在治疗阿尔茨海默病方面是有效的。然而，美金刚耐受性的机制仍然存在争议，但可能部分原因是它的非竞争性拮抗作用。NMDAR通道中美金刚阻滞剂的特定位置与镁相互作用，并被假设在代表通道选择性过滤器的狭窄狭窄处或附近。第二个极低亲和力的美金刚作用部位也已有报道。在这里，我们使用突变分析和取代半胱氨酸可及性方法对在非洲爪哇卵母细胞中表达的重组NR1/NR2ANMDARs进行精确定位。有趣的是，美金刚与其特定的阻断部位的作用方式与细胞内的镁离子相同，而不是细胞外的镁离子。因此，NR1亚基M2区的N位天冬酰胺(N)代表了美金刚非竞争性拮抗的优势部位。NR2A中的N位和N+1位天冬酰胺与美金胺产生较强的静电相互作用。相反，位于通道细胞外前庭的第二个(表面)美金刚阻断部位似乎是非特异性的，并与非特异性毛孔阻滞剂六甲溴铵所占据的部位重叠。NR1亚单位M3后片段的残基不直接参与美金刚的结合。不同的相互作用模式和美金刚对这两个结合部位的相对亲和力有助于该药在临床耐受性方面的出色药理学特征。今后，在寻找改善这类药物的神经保护剂时应考虑这些参数。
Unlike other N-methyl-D-aspartate receptor (NMDAR) antagonists, clinical trials have shown that memantine is clinically tolerated and effective in the treatment of Alzheimer's disease. The mechanism for memantine tolerability, however, remains contentious but may be partly explained by its uncompetitive antagonism. The specific site of memantine block in the NMDAR channel interacts with magnesium and is assumed to be at or near a narrow constriction representing the channel selectivity filter. A second, very low-affinity site of memantine action has also been reported. Here, using mutational analysis and substituted cysteine accessibility methods on recombinant NR1/NR2A NMDARs expressed in Xenopus oocytes, we precisely localize both the specific and second memantine-blocking sites. Intriguingly, memantine interacts with its specific blocking site in the same fashion as intracellular rather than extracellular Mg2+. Thus, the N-site asparagine (N) in the M2 region of the NR1 subunit represents the dominant site for uncompetitive antagonism by memantine. The N and N + 1 site asparagines in NR2A produce strong electrostatic interactions with memantine. In contrast, the second (superficial) memantine-blocking site, located at the extracellular vestibule of the channel, appears to be nonspecific and overlaps the site occupied by the nonspecific pore blocker hexamethonium. Residues in the post-M3 segment of the NR1 subunit are not directly involved in memantine binding. The distinct patterns of interaction and the relative degree of affinity of memantine for these two binding sites contribute to the drug's excellent pharmacological profile of clinical tolerability. In the future, these parameters should be considered in searching for improved neuroprotective agents in this class.