GluN2A-Selective NMDA Receptor Antagonists: Mimicking the U-Shaped Bioactive Conformation of TCN-201 by a [2.2]Paracyclophane System.
GluN2A-Selective NMDA Receptor Antagonists: Mimicking the U-Shaped Bioactive Conformation of TCN-201 by a [2.2]Paracyclophane System.
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DOI：
10.1002/cmdc.202200484
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发表时间：
2022-11-04
期刊：
影响因子：
3.4
通讯作者：
中科院分区：
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--
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在生理条件下，N-甲基-D-天冬氨酸（NMDA）受体在突触可塑性、长时程增强和长时程抑制中起着至关重要的作用。然而，NMDA受体的过度激活可导致兴奋性毒性，其与各种神经系统和神经退行性疾病相关。NMDA受体的生理特性强烈依赖于掺入异源四聚体NMDA受体的GluN 2亚基。因此，亚型选择性NMDA受体调节剂是高度感兴趣的。由于原型GluN 2A-NMDA受体拮抗剂TCN-201及其MPX-类似物在结合口袋内采用U形构象，因此设计了含有平行方向苯环的对环芳。所设计的对环芳的对接研究显示与TCN-201类似的结合位姿。[2.2]具有苯甲酸酯或苯甲酰胺侧链的对环芳分别在四步合成中制备，从[2.2]对环芳的苄基1-位的自由基溴化开始。在使用转染GluN 1 - 4a和GluN 2A亚基cRNA的非洲爪蟾卵母细胞的双电极电压钳实验中，酯和酰胺（浓度10 μM）未显示出对离子通量的显著抑制。 可以得出结论，GluN 2A-NMDA受体不接受具有在苄基1-位官能化的对环芳骨架的配体，尽管对接研究揭示了苯甲酸酯和苯甲酰胺的有希望的结合位。 在X射线晶体结构中，原型拮抗剂在含有NMDA受体的GluN 2A亚基的结合位点内采用U形构象。[2.2]设计并合成了对环番以模拟这种非常规构象。虽然对接研究显示有希望的结合姿势，离子通道的抑制是相当低的。
Under physiological conditions, N‐Methyl‐D‐Aspartate (NMDA) receptors play a crucial role for synaptic plasticity, long‐term potentiation and long‐term depression. However, overactivation of NMDA receptors can result in excitotoxicity, which is associated with various neurological and neurodegenerative diseases. The physiological properties of NMDA receptors are strongly dependent on the GluN2 subunit incorporated into the heterotetrameric NMDA receptor. Therefore, subtype selective NMDA receptor modulators are of high interest. Since prototypical GluN2A‐NMDA receptor antagonists TCN‐201 and its MPX‐analogs adopt a U‐shaped conformation within the binding pocket, paracyclophanes were designed containing the phenyl rings in an already parallel orientation. Docking studies of the designed paracyclophanes show a similar binding pose as TCN‐201. [2.2]Paracyclophanes with a benzoate or benzamide side chain were prepared in four‐step synthesis, respectively, starting with a radical bromination in benzylic 1‐position of [2.2]paracyclophane. In two‐electrode voltage clamp experiments using Xenopus laevis oocytes transfected with cRNAs for the GluN1‐4a and GluN2A subunits, the esters and amides (conc. 10 μM) did not show considerable inhibition of ion flux. It can be concluded that the GluN2A‐NMDA receptor does not accept ligands with a paracyclophane scaffold functionalized in benzylic 1‐position, although docking studies had revealed promising binding poses for benzoic acid esters and benzamides. In the X‐ray crystal structure, prototypical antagonists adopt a U‐shaped conformation within the binding site of GluN2A subunit containing NMDA receptors. [2.2]Paracyclophanes were designed and synthesized to mimic this unconventional conformation. Although docking studies revealed promising binding poses, the inhibition of the ion channel was rather low.
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