Piperazine-2,3-dicarboxylic Acid Derivatives as Dual Antagonists of NMDA and GluK1-Containing Kainate Receptors
Piperazine-2,3-dicarboxylic Acid Derivatives as Dual Antagonists of NMDA and GluK1-Containing Kainate Receptors
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DOI：
10.1021/jm201230z
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发表时间：
2012-01-12
影响因子：
7.3
通讯作者：
Jane, David E.
中科院分区：
文献类型：
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作者：
Irvine, Mark W.;Costa, Blaise M.;Jane, David E.
竞争性 N-甲基-D-天冬氨酸受体 (NMDAR) 拮抗剂与 GluN2 亚基结合，有四种类型 (GluN2A-D)。我们报道了顺式哌嗪-2,3-二甲酸的一些 N-1-取代衍生物对 GluN2C 和 GluN2D 的相对亲和力相对于 GluN2A 和 GluN2B 有所提高。这些衍生物还在关系较远的红藻氨酸受体家族中表现出亚型选择性。化合物 18i 和 (-)-4 是最有效的红藻氨酸受体拮抗剂，并且 18i 对 GluK1 相对于 GluK2、GluK3 和 AMPA 受体具有选择性。模型研究揭示了 GluK1 亚基活性所需的结构特征，并表明 S674 对于拮抗剂活性至关重要。与这一假设一致，用丝氨酸替换 GluK3（丙氨酸）中的等效残基可赋予 18i 拮抗剂活性。具有 GluN2D 和 GluK1 双重拮抗剂活性的拮抗剂可能对各种神经系统疾病产生有益作用。与这一想法一致，拮抗剂 18i（30 mg/kg ip）在轻度神经损伤的动物模型中显示出抗伤害作用。
Competitive N-methyl-D-aspartate receptor (NMDAR) antagonists bind to the GluN2 subunit, of which there are four types (GluN2A-D). We report that some N-1-substituted derivatives of cis-piperazine-2,3-dicarboxylic acid display improved relative affinity for GluN2C and GluN2D versus GluN2A and GluN2B. These derivatives also display subtype selectivity among the more distantly related kainate receptor family. Compounds 18i and (-)-4 were the most potent kainate receptor antagonists, and 18i was selective for GluK1 versus GluK2, GluK3 and AMPA receptors. Modeling studies revealed structural features required for activity at GluK1 subunits and suggested that S674 was vital for antagonist activity. Consistent with this hypothesis, replacing the equivalent residue in GluK3 (alanine) with a serine imparts 18i antagonist activity. Antagonists with dual GluN2D and GluK1 antagonist activity may have beneficial effects in various neurological disorders. Consistent with this idea, antagonist 18i (30 mg/kg ip) showed antinociceptive effects in an animal model of mild nerve injury.