基于NYX-2925 L-脯氨酸衍生的N-甲基-D-天冬氨酸(NMDA)受体部分激动剂的设计、合成和活性研究

Design,Synthesis and Bioactivity of NYX-2925 L-Proline Derivatives as N-Methyl-D-aspartate(NMDA)Receptor Partial Agonists

N-甲基-D-天冬氨酸(NMDA)受体属于配体门控离子型谷氨酸受体家族,是中枢神经系统中一种重要的兴奋性受体,与神经病理性疼痛、学习、记忆等密切相关.NYX-2925是一种新型的具有螺环β-内酰胺结构的二肽拟肽类NMDA受体部分激动剂先导化合物.本研究以NYX-2925的结构为基础,对其分子中L-脯氨酸片段进行了β-内酰胺环的开环衍生,设计并合成了3类共10个衍生物,所合成的化合物使用^(1)H NMR、^(13)C NMR、19F NMR和高分辨质谱(HRMS)进行了结构表征,并使用全细胞膜片钳技术测试了它们对人NMDA受体的激动效应.结果显示,大部分化合物对人NR1/NR2B NMDA受体均未表现出明显的激动作用,其中(R)-N-[(2S,3R)-1-氨基-3-羟基-1-氧代丁烷-2-基]-1-异丁酰基-2-苄基吡咯烷-2-甲酰胺(1g)显示出一定的拮抗作用,说明NYX-2925独特的螺环β-内酰胺二肽拟肽结构不是设计NMDA受体部分激动剂的理想先导结构,这一发现对未来基于NYX-2925这一独特结构的NMDA受体调节剂的研究方向具有重要的参考价值.

N-Methyl-D-aspartate(NMDA)receptors belong to a family of ligand-gated ionotropic glutamate receptors and represent an important class of excitary receptors in central nervous system,which are critical for neuropathic pain,learning and memory.NYX-2925 is a lead compound of NMDA receptor partial agonist which is essentially a dipeptide mimetic with a novel spirocyclicβ-lactam functionality.In the present study,10 novel derivatives of three different classes were designed based on NYX-2925 by a ring-opening strategy of the spirocyclicβ-lactam and synthesized.All these compounds were characterzied by ^(1)H NMR,^(13)C NMR,19F NMR and high-resolution mass spectrometery(HRMS),and subjected to an in vitro assay of their effect on human NR1/NR2B NMDA receptor current determined by whole-cell manual patch-clamp technique.The preliminary results indicated that both NYX-2925 and the synthesized 10 compounds displayed no significant effects on NMDA receptor except(R)-N-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-2-benzyl-1-isobutyrylpyrrolidine-2-carboxamide(1g)displayed a moderate antagonistic effect,suggesting that the unique structure of NYX-2925 is not a preferred lead structure for the design of NMDA receptor partial agonists.The findings revealed in the present study should be valuable for the future design of NMDA receptor modulators based on the novel structure of dipeptide mimetic with a novel spirocyclicβ-lactam represented by NYX-2925.