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

doi:10.6023/cjoc202310010

Chinese Journal of Organic Chemistry ›› 2024, Vol. 44 ›› Issue (4): 1247-1263.DOI: 10.6023/cjoc202310010 Previous Articles Next Articles

ARTICLES

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

吴游金^a^,^b, 金正盛^b, 刘咏嘉^b^,^c^,^d, 黄文倩^b^,^c^,^d, 赵桂龙^a^,^b^,^c^,^d^,^*()

a 遵义医科大学药学院贵州遵义 563003
b 中科中山药物创新研究院广东中山 528400
c 中国科学院上海药物研究所上海 201203
d 中国科学院大学北京 100049

收稿日期:2023-10-14 修回日期:2023-11-15 发布日期:2023-12-15
作者简介:† 共同第一作者.
基金资助:
中山市自然科学基金(200805173640573); 中山市自然科学基金(210730214049987); 广东省基础与应用基础研究基金(2021A1515010197); 广东省基础与应用基础研究基金(2023A1515012259); 中山市引进创新科研团队(CXTD2022011)

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

Youjin Wu^a^,^b, Zhengsheng Jin^b, Yongjia Liu^b^,^c^,^d, Wenqian Huang^b^,^c^,^d, Guilong Zhao^a^,^b^,^c^,^d()

a School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563003
b Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong 528400
c Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
d University of Chinese Academy of Sciences, Beijing 100049

Received:2023-10-14 Revised:2023-11-15 Published:2023-12-15
Contact: * E-mail: zhao_guilong@126.com
About author:† The authors contributed equally to this work.
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)

1. .pdf(37472KB)

Abstract

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.

Key words: N-methyl-D-aspartate (NMDA) receptor, partial agonist, NYX-2925, synthesis, bioactivity

Cite this article

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.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 6

References 30

[1]	Sheldon B. L.; Olmsted Z. T.; Sabourin S.; Heydari E.; Harland T. A.; Pilitsis J. G. Brain Sci. 2022, 12, 1727. doi: 10.3390/brainsci12121727
[2]	Mitsikostas D.-D.; Moka E.; Orrillo E.; Aurilio C.; Vadalouca A.; Paladini A.; Varrassi. G. Cureus 2022, 14, e22419.
[3]	Haanpaa M. L.; Backonja M. M.; Bennett M. I.; Bouhassira D.; Cruccu G.; Hansson P. T.; Jensen T. S.; Kauppila T.; Rice A. S. C.; Smith B. H.; Treede R. D.; Baron R. Am. J. Med. 2009, 122, S13. doi: 10.1016/j.amjmed.2009.04.006
[4]	Finnerup N. B.; Attal N.; Haroutounian S.; McNicol E.; Baron R.; Dworkin R. H.; Gilron I.; Haanpaa M.; Hansson P.; Jensen T. S.; Kamerman P. R.; Lund K.; Moore A.; Raja S. N.; Rice A. S. C.; Rowbotham M.; Sena E.; Siddall P.; Smith B. H.; Wallace M. Lancet Neurol. 2015, 14, 162. doi: 10.1016/S1474-4422(14)70251-0
[5]	Karakas E.; Furukawa H. Science 2014, 34, 992.
[6]	Vyklicky V.; Korinek M.; Smejkalova T.; Balik A.; Krausova B.; Kaniakova M.; Lichnerova K.; Cerny J.; Krusek J.; Dittert I.; Horak M.; Vyklicky L. Physiol. Res. 2014, 63, S191. doi: 10.33549/physiolres.932678 pmid: 24564659
[7]	Ultenius C.; Linderoth B.; Meyerson B. A.; Wallin J. Neurosci. Lett. 2009, 399, 85. doi: 10.1016/j.neulet.2006.01.018
[8]	Traynelis S. F.; Wollmuth L. P.; McBain C. J; Menniti F. S.; Vance K. M.; Ogden K. K.; Hansen K. B.; Yuan H. J.; Myers S. J.; Dingledine R. Pharmacol. Rev. 2010, 62, 2010.
[9]	Lefevre Y.; Amadioa A.; Vincent P.; Descheemaeker A.; Oliet S. H. R.; Dallel R.; Voisin D. L. Neurosci. Lett. 2015, 603, 42. doi: 10.1016/j.neulet.2015.07.010
[10]	Collins S.; Sigtermans M. J.; Dahan A.; Zuurmond W. W. A.; Perez R. S. G. M. Pain Med. 2010, 11, 1726. doi: 10.1111/j.1526-4637.2010.00981.x pmid: 21044263
[11]	Parsons C. G. Eur. J. Pharmacol. 2001, 429, 71. pmid: 11698028
[12]	Hood W.F.; Compton R. P.; Monahan J. B. Neurosci. Lett. 1989, 98, 91. pmid: 2540460
[13]	Wood P. L.; Mahmood S. A.; Moskal J. R. NeuroReport 2008, 19, 1061.
[14]	Ghoreishi-Haack N.; Priebe J. M.; Aguado J. D.; Colechio E. M.; Burgdorf J. S.; Bowers M. S.; Cearley C. N.; Khan M. A.; Moskal J. R. J. Pharmacol. Exp. Ther. 2018, 366, 485. doi: 10.1124/jpet.118.249409 pmid: 29986951
[15]	Goettig P.; Koch N. G.; Budisa N. Int. J. Mol. Sci. 2023, 24, 14035. doi: 10.3390/ijms241814035
[16]	Xiong B.; Wang Y.; Chen Y.; Xing S.; Liao Q.; Chen Y.; Li Q.; Li W.; Sun H. J. Med. Chem. 2021, 64, 13152. doi: 10.1021/acs.jmedchem.1c00910
[17]	Madsen T. M.; Khan M. A.; Arghavani M.; Bauer P.; Mar E. US 20210139489, 2021.
[18]	Harris P. W. R.; Brimble M. A.; Muir V. J.; Lai M. Y. H.; Callis D. J. Tetrahedron 2005, 61, 10018. doi: 10.1016/j.tet.2005.08.026
[19]	Hu D.; Han G.; Li X.; Ren H.; Yue L.; Guo L.; Feng J. Chin. J. Org. Chem. 2022, 42, 1863. (in Chinese) doi: 10.6023/cjoc202112015
	(胡冬燕, 韩广田, 李喜安, 任华忠, 岳李荣, 郭力, 封家福, 有机化学, 2022, 42, 1863.) doi: 10.6023/cjoc202112015
[20]	Hiroaki O.; Yasushi I.; Shun-Ichi M. Bull. Chem. Soc. Jpn. 1999, 72, 2737. doi: 10.1246/bcsj.72.2737
[21]	Leroy J.; Porhiel E.; Bondon A. Tetrahedron 2002, 58, 6713. doi: 10.1016/S0040-4020(02)00677-4
[22]	Mykhailiuk P. K.; Kubyshkin V.; Bach T.; Budisa N. J. Org. Chem. 2017, 82, 8831. doi: 10.1021/acs.joc.7b00803 pmid: 28590735
[23]	Pothula S.; Kato T.; Liu R.-J.; Wu M.; Gerhard D.; Shinohara R.; Sliby A.-N.; Chowdhury G. M. I.; Behar K. L.; Sanacora G.; Banerjee P.; Duman R. S. Mol. Psychiatr. 2021, 26, 5097. doi: 10.1038/s41380-020-0796-3
[24]	Lodge D.; Watkins J. C.; Bortolotto Z. A.; Jane D. E.; Volianskis A. Neurochem. Res. 2019, 44, 516. doi: 10.1007/s11064-018-2640-6 pmid: 30284673
[25]	Amedjkouh M.; Ahlberg P. Tetrahedron: Asymmetry 2002, 13, 2229.
[26]	Feng S.; Liang C. E.; Liu Y. F.; Shen H.; Tan X. F; Wu J.; Chen D. D.; Li C.; Wang, L. WO 2020053249, 2020.
[27]	Shinada T.; Yoshida H.; Ohfune Y. Synthesis 2009, 22, 3751.
[28]	Macharia J.; Wambua V.; Hong Y.; Harris L.; Hirschi J. S.; Evans G. B.; Vetticatt M. J. Angew. Chem., nt. Ed. 2017, 56, 8756.
[29]	Hughes P.; Clardy J. J. Org. Chem. 1988, 53, 4795.
[30]	Khan M. A.; Brodowaski, M. WO 2017201285, 2017.

Compound^a	Proportion of current compared to baseline level^b
Compound^a	0.1 μmol•L^–1	1.0 μmol•L^–1	10 μmol•L^–1	100 μmol•L^–1
D-cycloserine	106.51%	120.92%	165.30%	—
NYX-2925	110.53%	114.27%	108.02%	—
D-AP5	—	—	—	4.40%
1a	118.53%	117.24%	107.06%	—
1b	103.96%	118.63%	106.68%	—
1c	107.11%	97.65%	103.52%	—
1d	128.84%	113.33%	113.46%	—
1e	104.77%	99.94%	96.87%	—
1f	118.85%	101.72%	106.26%	—
1g	102.61%	95.35%	68.75%	—
1h	100.21%	118.91%	116.53%	—
1i	95.46%	99.06%	101.45%	—
1j	118.70%	108.60%	114.45%	—

Compound^a	Proportion of current compared to baseline level^b
Compound^a	0.1 μmol•L^–1	1.0 μmol•L^–1	10 μmol•L^–1	100 μmol•L^–1
D-cycloserine	106.51%	120.92%	165.30%	—
NYX-2925	110.53%	114.27%	108.02%	—
D-AP5	—	—	—	4.40%
1a	118.53%	117.24%	107.06%	—
1b	103.96%	118.63%	106.68%	—
1c	107.11%	97.65%	103.52%	—
1d	128.84%	113.33%	113.46%	—
1e	104.77%	99.94%	96.87%	—
1f	118.85%	101.72%	106.26%	—
1g	102.61%	95.35%	68.75%	—
1h	100.21%	118.91%	116.53%	—
1i	95.46%	99.06%	101.45%	—
1j	118.70%	108.60%	114.45%	—

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

RichHTML

PDF

Supporting Info.

Knowledge

Abstract

Cite this article

share this article

Fig. & Tab. 6

References 30

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	Hao Ye, Haibin Zhang, Ya'nan Wu, Xinxing Wu. Research Progress in the Synthesis of Azaindoline and Its Derivatives [J]. Chinese Journal of Organic Chemistry, 2024, 44(4): 1106-1123.
[2]	Xiao Zhang, Mixia Hu, Yanqing Du, Fengying Liang, Xiaoying Zhang, Chaolu Eerdun. Research Progress on Anion-π Interactions [J]. Chinese Journal of Organic Chemistry, 2024, 44(4): 1181-1196.
[3]	Tianfeng Peng, Yuxiang Zhao, Shaojian Pu, Juan Luo, Teng Liu, Yingchun Miao, Xianfu Shen. Recent Advances in Total Synthesis of Prenylated Indole Alkaloids by Transition Metal-Catalyzed Reactions as the Key Step [J]. Chinese Journal of Organic Chemistry, 2024, 44(4): 1160-1180.
[4]	Kejin Huang, Jinbo Cai, Ruige Wang, Yonghong Zhang, Bin Wang, Yu Xia, Weiwei Jin, Xinyong Li, Chenjiang Liu. Electrochemical C(sp²)—H Bromination of Glycine Derivatives Enabled by Boron [J]. Chinese Journal of Organic Chemistry, 2024, 44(3): 989-996.
[5]	Linheng He, Wen Xia, Yuxiang Zhou, Xianyong Yu. Electrocatalysis Decarboxylative Annulation of Benzol[e][1,2,3]-oxathiazine-2,2-dioxides with N-Arylglycines [J]. Chinese Journal of Organic Chemistry, 2024, 44(3): 997-1004.
[6]	Ruilin Gao, Lirong Wen, Weisi Guo. Recent Advances in Electrochemical-Promoted Unactivated C(sp³)—H Functionalization [J]. Chinese Journal of Organic Chemistry, 2024, 44(3): 892-902.
[7]	Yuanhang Chen, Jinyu He, Bo Zhang, Yanzhao Wang, Lingxuan Kong, Weifeng Qian, Na'na Wang, Wenxi Duan, Yanyan Ouyang, Cuiju Zhu, Hao Xu. Asymmetric Electrochemical Organic Synthesis [J]. Chinese Journal of Organic Chemistry, 2024, 44(3): 748-779.
[8]	Zenghui Ye, Huaqing Liu, Fengzhi Zhang. Recent Advances in Organic Electrophotocatalytic Synthesis [J]. Chinese Journal of Organic Chemistry, 2024, 44(3): 840-870.
[9]	Luyao Han, Shuozhen Hu, Qingchun Guo, Hongyong Guo, Zhaoqun Gao, Ying Xu, Xinsheng Zhang. Study on Electrooxidation of Benzophenone Hydrazone to Diphenyldiazomethane [J]. Chinese Journal of Organic Chemistry, 2024, 44(3): 951-965.
[10]	Chun Gao, Xin Liu, Minghui Wang, Shuxian Liu, Tingting Zhu, Yikang Zhang, Erjun Hao, Qiliang Yang. Advances in Asymmetric Electrochemical Synthesis [J]. Chinese Journal of Organic Chemistry, 2024, 44(3): 673-727.
[11]	Fan Yang, Ting Fang, Guichun Yang, Meng Gao. Electrochemical Cascade Cyclization Reactions of Nitrosobenzenes in Construction of Quinolines and Pyrroles [J]. Chinese Journal of Organic Chemistry, 2024, 44(3): 1021-1030.
[12]	Penghui Li, Qingyang Xie, Fuxian Wan, Yuanhong Zhang, Lin Jiang. Synthesis and Fungicidal Activity of Novel Substituted Pyrimidine-5-carboxamides Bearing Cyclopropyl Moiety [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 650-656.
[13]	Fakai Zou, Nengzhong Wang, Hui Yao, Hui Wang, Mingguo Liu, Nianyu Huang. Regio- and Stereo-selective Synthesis of 1β-/3R-Aryl Thiosugar [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 593-604.
[14]	Luyao Li, Zhongwen He, Zhenguo Zhang, Zhenhua Jia, Teck-Peng Loh. Application of Triaryl Carbenium in Organic Synthesis [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 421-437.
[15]	Qinggang Mei, Qinghan Li. Recent Progress of Visible Light-Induced the Synthesis of C(3) (Hetero)arylthio Indole Compounds [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 398-408.