Mechanism of inhibition of the GluA1 AMPA receptor channel opening by the 2,3-benzodiazepine compound GYKI 52466 and a N-methyl-carbamoyl derivative.
Mechanism of inhibition of the GluA1 AMPA receptor channel opening by the 2,3-benzodiazepine compound GYKI 52466 and a N-methyl-carbamoyl derivative.
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DOI：
10.1021/bi5002079
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发表时间：
2014-05-13
期刊：
影响因子：
2.9
通讯作者：
Niu L
中科院分区：
文献类型：
--
作者：
Wu A;Wang C;Niu L
2，3-苯并二氮杂卓类化合物，又称GYKI类化合物，是一类最有前途的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的合成抑制剂。在这里，我们研究了GYKI 52466及其N-3甲基氨基甲酰基衍生物（我们称之为BDZ-f）抑制GluA 1通道开放的机制和抑制位点。GluA 1是参与脑功能的关键AMPA受体亚单位。然而，GluA 1的过度活性和表达升高与许多神经系统疾病有关。使用激光脉冲光解技术，提供了1060 μs的分辨率，我们测量了这些抑制剂对GluA 1通道开放速率和谷氨酸诱导的全细胞电流幅度的影响。我们发现，这两种化合物抑制GluA 1通道非竞争性。将N-3甲基-氨基甲酰基加到具有甲亚胺特征的二氮杂环上（即，GYKI 52466）提高了所得化合物或BDZ-f的效力，而不改变结合位点。该位点，我们以前称为GluA 2 AMPA受体亚基上的“M”位点，因此有利地容纳N-3酰化基团。基于相同抑制剂但不同受体的抑制常数的大小，GluA 1和GuA 2上的“M”位点是不同的。总体而言，“M”位点或GluA 2上的结合环境更好地容纳相同的化合物，或者相同的抑制剂对GluA 2显示出更强的效力，正如我们之前报道的那样[Wang et al.（），−]。然而，酰化N-3位以占据“M”位点的N-3侧袋可显著缩小差异并提高所得化合物对GluAl的效力。
2,3-Benzodiazepine derivatives, also known as GYKI compounds, represent a group of the most promising synthetic inhibitors of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Here we investigate the mechanism of inhibition of the GluA1 channel opening and the site of inhibition by GYKI 52466 and its N-3 methyl-carbamoyl derivative, which we term as BDZ-f. GluA1 is a key AMPA receptor subunit involved in the brain function. Excessive activity and elevated expression of GluA1, however, has been implicated in a number of neurological disorders. Using a laser-pulse photolysis technique, which provides ∼60 μs resolution, we measured the effect of these inhibitors on the rate of GluA1 channel opening and the amplitude of the glutamate-induced whole-cell current. We found that both compounds inhibit GluA1 channel noncompetitively. Addition of an N-3 methyl-carbamoyl group to the diazepine ring with the azomethine feature (i.e., GYKI 52466) improves the potency of the resulting compound or BDZ-f without changing the site of binding. This site, which we previously termed as the “M” site on the GluA2 AMPA receptor subunit, therefore favorably accommodates an N-3 acylating group. On the basis of the magnitude of the inhibition constants for the same inhibitors but different receptors, the “M” sites on GluA1 and GuA2 are different. Overall, the “M” site or the binding environment on GluA2 accommodates the same compounds better, or the same inhibitors show stronger potency on GluA2, as we have reported previously [Wang et al. () , −]. However, acylating the N-3 position to occupy the N-3 side pocket of the “M” site can significantly narrow the difference and improve the potency of a resulting compound on GluA1.
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影响因子：
5.3
作者：
Partin, KM;Fleck, MW;Mayer, ML
通讯作者：
Mayer, ML
影响因子：
5
作者：
Ritz, Mark;Wang, Congzhou;Niu, Li
通讯作者：
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影响因子：
3.4
作者：
Katano, Tayo;Furue, Hidemasa;Ito, Seiji
通讯作者：
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影响因子：
2.9
作者：
Li, G;Pei, WM;Niu, L
通讯作者：
Niu, L
DOI：
10.1073/pnas.96.6.3269
发表时间：
1999-03-16
影响因子：
11.1
作者：
Derkach, V;Barria, A;Soderling, TR
通讯作者：
Soderling, TR