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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Cyclophane and acyclic cyclophane: novel channel blockers of N-methyl-D-aspartate receptor.
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Cyclophane and acyclic cyclophane: novel channel blockers of N-methyl-D-aspartate receptor.

机译：环环烷和无环环烷：N-甲基-D-天冬氨酸受体的新型通道阻滞剂。

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摘要

The effects of cyclophanes (CPCn, CPPy and TGDMAP) and acyclic cyclophane (ATGDMAP) on various glutamate receptors were studied with these receptors expressed in Xenopus oocytes using voltage-clamp recording. CPCn, CPPy, TGDMAP and ATGDMAP were found to inhibit macroscopic currents at heteromeric NMDA receptors (NR1/NR2), but not Ca(2+)-permeable AMPA receptors (GluR1), Ca(2+)-nonpermeable AMPA receptors (GluR1/GluR2) and metabotropic glutamate receptors (mGluR1alpha). The inhibition of NR1/NR2A receptors by these compounds was more potent than those of the other NMDA receptor subtypes. At a resting potential (-70 mV), the IC(50) values of CPCn, CPPy, TGDMAP and ATGDMAP for NR1/NR2A receptors were 0.5+/-0.1, 1.0+/-0.2, 8.0+/-0.8 and 4.9+/-0.5 microM, respectively. The inhibition by these compounds was voltage-dependent, that is, the degree of inhibition was in the order of negative holding potentials, -100 mV>-70 mV>-20 mV. Results of experiments using mutant NR1 and NR2 subunits identified residues that influence block by CPCn. The inhibition by CPCn was not altered significantly in the mutants at the critical asparagines in the M2 loop, NR1 N616, NR2B N615 and NR2B N616, these residues are known to form the narrowest region of the channel and the binding site of Mg(2+). However, mutations at NR1 N650, located in the vestibule of channel pore, and NR1 D669, located in the extracellular region, reduced the inhibition by CPCn, suggesting that these amino acid residues interact with CPCn. These results suggest that CPCn interacts directly with the mouth or vestibule of the ion channel, like a lid.
机译：利用爪蟾卵母细胞中的这些受体，通过电压钳记录研究了环戊烯（CPCn，CPPy和TGDMAP）和无环环烷（ATGDMAP）对各种谷氨酸受体的影响。发现CPCn，CPPy，TGDMAP和ATGDMAP抑制异聚NMDA受体（NR1 / NR2）的宏观电流，但不抑制Ca（2+）渗透性AMPA受体（GluR1），Ca（2+）渗透性AMPA受体（GluR1 / GluR2）和代谢型谷氨酸受体（mGluR1alpha）。这些化合物对NR1 / NR2A受体的抑制作用比其他NMDA受体亚型的抑制作用更强。在静止电位（-70 mV）下，NR1 / NR2A受体的CPCn，CPPy，TGDMAP和ATGDMAP的IC（50）值为0.5 +/- 0.1、1.0 +/- 0.2、8.0 +/- 0.8和4.9+分别为--0.5 microM。这些化合物的抑制是电压依赖性的，即抑制程度为负保持电位的顺序，即-100mV＞ -70mV＞ -20mV。使用突变体NR1和NR2亚基的实验结果确定了残基会影响CPCn的残基。 CPCn的抑制作用在M2环的关键天门冬酰胺突变体NR1 N616，NR2B N615和NR2B N616中没有显着改变，已知这些残基形成通道的最窄区域和Mg（2+ ）。但是，位于通道孔前庭的NR1 N650和位于细胞外区域的NR1 D669的突变降低了CPCn的抑制作用，表明这些氨基酸残基与CPCn相互作用。这些结果表明，CPCn与离子通道的嘴或前庭直接相互作用，就像盖子一样。

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