Chinese Journal of Organic Chemistry >
Design, Synthesis and Bioactivity of NYX-2925 L-Proline Derivatives as N-Methyl-D-aspartate (NMDA) Receptor Partial Agonists
Received date: 2023-10-14
Revised date: 2023-11-15
Online published: 2023-12-18
Supported by
Zhongshan Municipal Natural Science Foundation(200805173640573); Zhongshan Municipal Natural Science Foundation(210730214049987); Guangdong Basic and Applied Basic Research Foundation(2021A1515010197); Guangdong Basic and Applied Basic Research Foundation(2023A1515012259); Creative Research Group of Zhongshan City(CXTD2022011)
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 spirocyclic β-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 spirocyclic β-lactam and synthesized. All these compounds were characterzied by 1H NMR, 13C 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 spirocyclic β-lactam represented by NYX-2925.
Youjin Wu , Zhengsheng Jin , Yongjia Liu , Wenqian Huang , Guilong Zhao . Design, Synthesis and Bioactivity of NYX-2925 L-Proline Derivatives as N-Methyl-D-aspartate (NMDA) Receptor Partial Agonists[J]. Chinese Journal of Organic Chemistry, 2024 , 44(4) : 1247 -1263 . DOI: 10.6023/cjoc202310010
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