[2.2]Paracyclophane-Based TCN-201 Analogs as GluN2A-Selective NMDA Receptor Antagonists.
[2.2]Paracyclophane-Based TCN-201 Analogs as GluN2A-Selective NMDA Receptor Antagonists.
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DOI：
10.1002/cmdc.202100400
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发表时间：
2021-10-15
期刊：
影响因子：
3.4
通讯作者：
Wünsch B
中科院分区：
文献类型：
--
作者：
Rajan R;Schepmann D;Steigerwald R;Schreiber JA;El-Awaad E;Jose J;Seebohm G;Wünsch B
最近的研究表明含有GluN2A亚基的NMDA受体参与多种神经和病理疾病。在X射线晶体结构中，TCN - 201(1)和类似的吡嗪衍生物2和3在GluN1和GluN2A亚基的配体结合域形成的结合位点内呈U形（发夹）构象。为了模拟两个芳香环在结合位点的π/π‐相互作用，设计了一个[2.2]副环环烷系统，将这些芳香环锁定在平行方向上。[2.2]副环环烷(5)与草酰氯和氯乙酰氯的酰化以及随后的转化产生了草酰胺7、三唑10和苯酰胺12。利用带GluN2A亚基的功能性NMDA受体的非洲爪蟾卵母细胞，采用双电极电压钳电生理学方法检测了副环环烷衍生物的GluN2A抑制活性。与TCN - 201相似度最高的o -碘苯甲酰胺12b显示出该系列化合物中最高的GuN2A抑制活性。在10 μM的浓度下，12b达到TCN‐201的36%的抑制活性(1)。这一结果表明[2.2]副环烷体系被TCN‐201结合位点所接受。在结晶的GluN1/GluN2A配体结合域的结合口袋中，原型拮抗剂TCN‐201和类似物呈U形构象。[2.2]基于paraccyclophane的GluN2A拮抗剂被设计成模拟TCN‐201在结合袋中的U形构象。合成的苯甲酰胺具有TCN‐201 36%的GluN2A抑制活性，证实了含有[2.2]副环环烷系统的化合物被GluN2A‐NMDA受体很好地接受。
Recent studies have shown the involvement of GluN2A subunit‐containing NMDA receptors in various neurological and pathological disorders. In the X‐ray crystal structure, TCN‐201 (1) and analogous pyrazine derivatives 2 and 3 adopt a U‐shape (hairpin) conformation within the binding site formed by the ligand binding domains of the GluN1 and GluN2A subunits. In order to mimic the resulting π/π‐interactions of two aromatic rings in the binding site, a [2.2]paracyclophane system was designed to lock these aromatic rings in a parallel orientation. Acylation of [2.2]paracyclophane (5) with oxalyl chloride and chloroacetyl chloride and subsequent transformations led to the oxalamide 7, triazole 10 and benzamides 12. The GluN2A inhibitory activities of the paracyclophane derivatives were tested with two‐electrode voltage clamp electrophysiology using Xenopus laevis oocytes expressing selectively functional NMDA receptors with GluN2A subunit. The o‐iodobenzamide 12 b with the highest similarity to TCN‐201 showed the highest GuN2A inhibitory activity of this series of compounds. At a concentration of 10 μM, 12 b reached 36 % of the inhibitory activity of TCN‐201 (1). This result indicates that the [2.2]paracyclophane system is well accepted by the TCN‐201 binding site. In the binding pocket of crystallized GluN1/GluN2A ligand binding domain, the prototypical antagonist TCN‐201 and analogs adopt a U‐shaped conformation. [2.2]Paracyclophane‐based GluN2A antagonists were designed to mimic the U‐shaped conformation of TCN‐201 in the binding pocket. The synthesized benzamide shown here possesses 36 % of the GluN2A inhibitory activity of TCN‐201, confirming that compounds with the [2.2]paracyclophane system are well accepted by GluN2A‐NMDA receptors.
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