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首页> 外文OA文献 >N-Methyl-d-aspartate (NMDA) Receptor NR2 Subunit Selectivity of a Series of Novel Piperazine-2,3-dicarboxylate Derivatives: Preferential Blockade of Extrasynaptic NMDA Receptors in the Rat Hippocampal CA3-CA1 Synapse
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N-Methyl-d-aspartate (NMDA) Receptor NR2 Subunit Selectivity of a Series of Novel Piperazine-2,3-dicarboxylate Derivatives: Preferential Blockade of Extrasynaptic NMDA Receptors in the Rat Hippocampal CA3-CA1 Synapse

机译：N-甲基-d-天门冬氨酸（NMDA）受体NR2亚基选择性的一系列新型哌嗪2,3-二羧酸酯衍生物：大鼠海马CA3-CA1突触中突触外NMDA受体的优先阻断。

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摘要

N-Methyl-d-aspartate (NMDA) receptor antagonists that are highly selective for specific NMDA receptor 2 (NR2) subunits have several potential therapeutic applications; however, to date, only NR2B-selective antagonists have been described. Whereas most glutamate binding site antagonists display a common pattern of NR2 selectivity, NR2A > NR2B > NR2C > NR2D (high to low affinity), (2S*,3R*)-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA) has a low selectivity for NR2C- and NR2D-containing NMDA receptors. A series of PPDA derivatives were synthesized and then tested at recombinant NMDA receptors expressed in Xenopus laevis oocytes. In addition, the optical isomers of PPDA were resolved; the (−) isomer displayed a 50- to 80-fold greater potency than the (+) isomer. Replacement of the phenanthrene moiety of PPDA with naphthalene or anthracene did not improve selectivity. However, phenylazobenzoyl (UBP125) or phenylethynylbenzoyl (UBP128) substitution significantly improved selectivity for NR2B-, NR2C-, and NR2D-containing receptors over NR2A-containing NMDA receptors. Phenanthrene attachment at the 3 position [(2R*,3S*)-1-(phenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid (UBP141); (2R*,3S*)-1-(9-bromophenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid (UBP145); (2R*,3S*)-1-(9-chlorophenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid (UBP160); and (2R*,3S*)-1-(9-iodophenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid (UBP161)] displayed improved NR2D selectivity. UBP141 and its 9-brominated homolog (UBP145) both display a 7- to 10- fold selectivity for NR2D-containing receptors over NR2B- or NR2A-containing receptors. Schild analysis indicates that these two compounds are competitive glutamate binding site antagonists. Consistent with a physiological role for NR2D-containing receptors in the hippocampus, UBP141 (5 μM) displayed greater selectivity than PPDA for inhibiting the slow-decaying component of the NMDA receptor-mediated CA3-CA1 synaptic response in rat hippocampal slices. UBP125, UBP128, UBP141, and UBP145 may be useful tools for determining the function of NMDA receptor subtypes.
机译：对特定的NMDA受体2（NR2）亚基具有高度选择性的N-甲基-d-天冬氨酸（NMDA）受体拮抗剂具有多种潜在的治疗应用。然而，迄今为止，仅描述了NR2B选择性拮抗剂。多数谷氨酸结合位点拮抗剂表现出常见的NR2选择性模式，NR2A> NR2B> NR2C> NR2D（高至低亲和力），（2S *，3R *）-1-（菲-2-羰基）哌嗪-2,3 -二羧酸（PPDA）对含有NR2C和NR2D的NMDA受体的选择性低。合成了一系列的PPDA衍生物，然后在非洲爪蟾卵母细胞中表达的重组NMDA受体上进行了测试。此外，还解决了PPDA的旋光异构体问题。 （-）异构体的效能比（+）异构体高50至80倍。用萘或蒽代替PPDA的菲部分不会提高选择性。但是，与含NR2A的NMDA受体相比，苯偶氮苯甲酰基（UBP125）或苯乙炔基苯甲酰基（UBP128）取代显着提高了对NR2B，NR2C和NR2D受体的选择性。在3位[（2R *，3S *）-1-（菲-3-羰基）哌嗪-2,3-二羧酸（UBP141）; （2R *，3S *）-1-（9-溴菲-3-羰基）哌嗪-2,3-二羧酸（UBP145）; （2R *，3S *）-1-（9-氯菲-3-羰基）哌嗪-2,3-二羧酸（UBP160）; （2R *，3S *）-1-（9-碘菲-3-羰基）哌嗪-2,3-二羧酸（UBP161）]显示出改进的NR2D选择性。与含有NR2B或NR2A的受体相比，UBP141及其9溴同系物（UBP145）的选择性都高出7至10倍。 Schild分析表明这两种化合物是竞争性谷氨酸结合位点拮抗剂。与海马中含有NR2D的受体的生理作用一致，UBP141（5μM）在抑制大鼠海马切片中NMDA受体介导的CA3-CA1突触反应的缓慢衰减成分方面表现出比PPDA更大的选择性。 UBP125，UBP128，UBP141和UBP145可能是确定NMDA受体亚型功能的有用工具。

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