Structure-activity analysis of a novel NR2C/NR2D-preferring NMDA receptor antagonist: 1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid
Structure-activity analysis of a novel NR2C/NR2D-preferring NMDA receptor antagonist: 1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid
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DOI：
10.1038/sj.bjp.0705644
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发表时间：
2004-02-01
影响因子：
7.3
通讯作者：
Monaghan, DT
中科院分区：
文献类型：
--
作者：
Feng, BH;Tse, HW;Monaghan, DT
1（2S*，3R*）-1-（联苯-4-羰基）哌嗪-2，3-二羧酸（PBPD）是一种中等亲和力的竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，对NMDA受体2亚基（NR 2）具有非典型的选择性。我们现在描述了几种PBPD衍生物的活性，这些衍生物使用L-[H-3]-谷氨酸结合试验对大鼠脑NMDA受体进行了测试，并对爪蟾卵母细胞中表达的重组受体进行了测试。2用各种支链结构取代PBPD的联苯基降低了NMDA受体活性。然而，取代线性排列的环结构-芴酮或菲基团-保留或增强活性。3相对于PBPD，菲衍生物（2S*，3R*）-1-（菲-2-羰基）哌嗪-2，3-二羧酸（PPDA）对天然NMDA受体的亲和力增加了30至78倍。在重组受体上，PPDA显示出比PBPD增加16倍（NR 2B）至94倍（NR 2C）的亲和力。4用9-氧代芴环系统取代PBPD的联苯基导致受体亲和力和亚型选择性的微小变化。5 PBPD的联苯基上的2 '-溴取代使NR 2A-，NR 2B和NR 2D受体，但对NR 2C受体几乎没有影响。相比之下，PBPD的联苯环的4 '-氟取代选择性地增加NR 2A亲和力。6 PBPD和PPDA的芳环增加拮抗剂亲和力，并且似乎与显示亚基异质性的NMDA受体区域相互作用。PPDA是迄今为止报道的最有效和选择性的NR 2C/NR 2D偏好拮抗剂，因此可能有助于定义NR 2C/NR 2D功能和开发具有改善的NMDA受体亚型选择性的相关拮抗剂。
1 (2S*,3R*)-1-(biphenyl-4-carbonyl)piperazine-2,3-dicarboxylic acid (PBPD) is a moderate affinity, competitive N-methyl-D-aspartate (NMDA) receptor antagonist with an atypical pattern of selectivity among NMDA receptor 2 subunit (NR2) subunits. We now describe the activity of several derivatives of PBPD tested at both rat brain NMDA receptors using L-[H-3]-glutamate binding assays and at recombinant receptors expressed in Xenopus oocytes.2 Substituting various branched ring structures for the biphenyl group of PBPD reduced NMDA receptor activity. However, substituting linearly arranged ring structures-fluorenone or phenanthrene groups-retained or enhanced activity.3 Relative to PBPD, the phenanthrene derivative (2S*,3R*)-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA) displayed a 30- to 78-fold increase in affinity for native NMDA receptors. At recombinant receptors, PPDA displayed a 16-fold (NR2B) to 94-fold (NR2C) increase in affinity over PBPD.4 Replacement of the biphenyl group of PBPD with a 9-oxofluorene ring system resulted in small changes in receptor affinity and subtype selectivity.5 2'-Bromo substitution on the biphenyl group of PBPD reduced antagonist affinity 3- to 5-fold at NR2A-, NR2B- and NR2D-containing receptors, but had little effect on NR2C-containing receptors. In contrast, 4'-fluoro substitution of the biphenyl ring of PBPD selectively increased NR2A affinity.6 The aromatic rings of PBPD and PPDA increase antagonist affinity and appear to interact with a region of the NMDA receptor displaying subunit heterogeneity. PPDA is the most potent and selective NR2C/NR2D-preferring antagonist yet reported and thus may be useful in defining NR2C/NR2D function and developing related antagonists with improved NMDA receptor subtype selectivity.