Design, Synthesis, and Activity of Novel N-2,3-Difluorophenyl Cyclobutylamine M4 AChR Positive Allosteric Modulators

doi:10.6023/cjoc202510015

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新型N-2,3-二氟苯基环丁胺类M4 AChR正向变构调节剂的设计、合成与活性

刘敏¹, 陈毅昆², 田峦鸢², 周海峰¹, 周皓^*,2, 刘祈星^*,1

(¹三峡大学生物与制药学院, 天然产物研究与利用湖北省重点实验室, 宜昌 443002)
(²宜昌人福药业有限责任公司, 宜昌 443005)

收稿日期:2025-10-22 修回日期:2025-12-24
基金资助:
国家自然科学基金(No. 22278244)和宜昌人福药业有限责任公司研发项目(SDHZ2023029)资助项目.

Design, Synthesis, and Activity of Novel N-2,3-Difluorophenyl Cyclobutylamine M4 AChR Positive Allosteric Modulators

Liu Min¹, Chen Yikun², Tian Luanyuan², Zhou Haifeng¹, Zhou Hao^*,2, Liu Qixing^*,1

(¹Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002)
(²Yichang Humanwell Pharmaceutical Co., Ltd., Yichang 443005)

Received:2025-10-22 Revised:2025-12-24
Contact: ^*E-mail: zhouhao@renfu.com.cn; qixingliu86@163.com.
Supported by:
Project supported by the National Natural Science Foundation of China (No. 22278244) and a research fund from Yichang Humanwell Pharmaceutical Co., Ltd. (SDHZ2023029).

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Abstract

Using VU6000918 as the lead compound, employing the Glide docking module of the Schrödinger platform to perform molecular docking and scoring evaluations of the designed target compounds with the allosteric binding sites of the M4 receptor protein, 27 N-2,3-difluorophenyl cyclobutylamine derivatives (V1-V27) were designed and synthesized. The activities of these compounds on M4 receptor cells were evaluated using FLIPR fluorescence detection technology. The results showed that some target compounds exhibited significant activities on M4 receptor cells. Among them, compounds V1 (EC₅₀ = 0.636 μM), V8 (EC₅₀ = 0.482 μM), V10 (EC₅₀ = 0.508 μM), and V13 (EC₅₀ = 0.621 μM) had higher or comparable activities on M4 receptor cells than the lead compound. Structure-activity relationship (SAR) studies revealed that compounds containing a quinoline ring exhibited higher activity. In particular, the compounds with a methyl group at the position 4 of the quinolone showed higher activities than those with other substituents, demonstrating that the introduction of the methyl group can significantly enhance the activity and is worthy of further investigation. Molecular-docking results indicate that these compounds can bind effectively to the allosteric site of the M4 receptor, thereby exerting their potential pharmacological effects. This work provides a guidance for the design of M4 AChR positive allosteric modulators.

Key words: molecular docking, M4 positive allosteric modulator, N-2,3-difluorophenyl cyclobutylamine, synthesis, activity

Cite this article

Liu Min, Chen Yikun, Tian Luanyuan, Zhou Haifeng, Zhou Hao, Liu Qixing. Design, Synthesis, and Activity of Novel N-2,3-Difluorophenyl Cyclobutylamine M4 AChR Positive Allosteric Modulators[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202510015.

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[1] Kennedy J. P.; Bridges T. M.; Gentry P. R.; Brogan J. T.; Kane A. S.; Jones C. K.; Brady A. E.; Shirey J. K.; Conn P. J.; Lindsley C. W. ChemMedChem,2009, 4, 1600.
[2] Clader J. W.; Wang, Y. Curr. Pharm. Des.,2005, 11, 3353.
[3] Langmead C. J.; Watson J.; Reavill C. Pharmacol. Ther.,2008, 117, 232.
[4] Wess J.; Eglen R. M.; Gautam, D. Nat. Rev. Drug Discov.,2007, 6, 721.
[5] Felder C. C.; Bymaster F. P.; Ward J.; DeLapp, N. J. Med. Chem.,2000, 43, 4333.
[6] Kaul I.; Sawchak S.; Correll C. U.; Kakar R.; Breier A.; Zhu H.; Miller A. C.; Paul S. M.; Brannan S. K. Lancet,2024, 403, 160.
[7] Azargoonjahromi, A. Clin. Drug Investig., 2024, 44, 471.
[8] Astori, V.; Pandolfi, Arruda, B.; Westphalen Pomianoski, B.; Lopes Vieira, D.; Prätzel Ellwanger, M.; Frizzo Messinger, M.; Fernandes Holanda, D.Eur. Psychiatry, 2025, 68, S1086.
[9] Brady A. E.; Jones C. K.; Bridges T. M.; Kennedy J. P.; Thompson A. D.; Heiman J. U.; Breininger M. L.; Gentry P. R.; Yin H.; Jadhav S. B.; Shirey J. K.; Conn P. J.; Lindsley, C. W. Phar. Exp. Ther.,2008, 327, 941.
[10] Chan W. Y.; McKinzie D. L.; Bose S.; Mitchell S. N.; Witkin J. M.; Thompson R. C.; Christopoulos A.; Lazareno S.; Birdsall N. J. M.; Bymaster F. P.; Felder C. C. PNAS,2008, 105, 10978.
[11] Farrell M.; Roth B. L. Neuropsychopharmacology,2010, 35, 851.
[12] Foster D. J.; Wilson J. M.; Remke D. H.; Mahmood M. S.; Uddin M. J.; Wess J.; Patel S.; Marnett L. J.; Niswender C. M.; Jones C. K.; Xiang Z.; Lindsley C. W.; Rook J. M.; Conn P. J. Neuron,2016, 91, 1244.
[13] Bauer M. R.; Fruscia P. D.; Luca S. C. C.; Michaelides I. N.; Nelson J. E.; Storer R. I.; Whitehurst, B. C. RSC Med. Chem.,2021, 12, 448.
[14] Mughal H.; Szostak, M. Org. Biomol. Chem.,2021, 19, 3274.
[15] Luo Y.; Qiu, Y.-L; Lin Y.; Li, Q.-X; Fu, L.-S; Xu, X.-Q; Shi, Y.-W; Lu, T.; Wei X.; Xu, X.-Y; Chen, Y.-D; Jiao, Y. Eur. J. Med. Chem.,2025, 298, 117993.
[16] Bubser M.; Bridges T. M.; Dencker D.; Gould R. W.; Grannan M.; Noetzel M. J.; Lamsal A.; Niswender C. M.; Daniels J. S.; Poslusney M. S.; Melancon B. J.; Tarr J. C.; Byers F. W.; Wess J.; Duggan M. E.; Dunlop J.; Wood M. W.; Brandon N. J.; Wood M. R.; Lindsley C. W.; Conn P. J.; Jones, C. K. ACS Chem. Neurosci.,2014, 5, 920.
[17] Wood M. R.; Noetzel M. J.; Poslusney M. S.; Melancon B. J.; Tarr J. C.; Lamsal A.; Chang S.; Luscombe V. B.; Weiner R. L.; Cho H. P.; Bubser M.; Jones C. K.; Niswender C. M.; Wood M. W.; Engers D. W.; Brandon N. J.; Duggan M. E.; Conn P. J.; Bridges T. M.; Lindsley, C. W. Bioorg. Med. Chem. Lett.,2017, 27, 171.
[18] Tarr J. C.; Wood M. R.; Noetzel M. J.; Bertron J.; Weiner R. L.; Rodriguez A. L.; Lamsal A.; Byers F. W.; Chang S.; Cho H. P.; Jones C. K.; Niswender C. M.; Wood M. W.; Brandon N. J.; Duggan M. E.; Conn P. J.; Bridges T. M.; Lindsley, C. W. Bioorg. Med. Chem. Lett.,2017, 27, 2990.
[19] Halgren T. A.; Murphy R. B.; Friesner R. A.; Beard H. S.; Frye L. L.; Pollard W. T.; Banks, J. L. J. Med. Chem.,2004, 47, 1750.
[20] Burger W. A. C.; Pham V.; Vuckovic Z.; Powers A. S.; Mobbs J. I.; Laloudakis Y.; Glukhova A.; Wootten D.; Tobin A. B.; Sexton P. M.; Paul S. M.; Felder C. C.; Danev R.; Dror R. O.; Christopoulos A.; Valant C.; Thal, D. M. Nat. Commun.,2023, 14, 5440.
[21] Wang C.-X.; Chang S.; Gong X.-Q.; Yang F.; Li C.-F.; Chen, W.-Z. Acta Phys.-Chim. Sin.,2012, 28, 751 (in Chinese)
(王存新, 常珊, 龚新奇, 杨峰, 李春华, 陈慰祖, 物理化学学报, 2012, 28, 751).
[22] Feng J.; Wang C.-Y.; Zhou C.-K.; Zuo H.-J.; Shen, Y.-J. Chin. J. Org. Chem.,2011, 31, 203 (in Chinese).
(封静, 王成云, 周长凯, 左虎进, 沈永嘉. 有机化学, 2011, 31, 203).
[23] Wolfe J. P.; Buchwald, S. L. J. Org. Chem.,2000, 65, 1144.
[24] Hartwig, J. F.Angew. Chem. Int. Ed., 1998, 37, 2046.
[25] Zhang Z.-F.; Zhou, W.-C. Chin. J. Org. Chem.,2002, 22, 685 (in Chinese).
(张贞发, 周伟澄. 有机化学, 2002, 22, 685).
[26] Jia Y.-L.; Wang, Y. Chin. J. Org. Chem.,2011, 31, 538 (in Chinese).
(贾尧玲, 王洋. 有机化学, 2011, 31, 538).
[27] Hoekstra M. S.; Sobieray D. M.; Schwindt M. A.; Mulhern T. A.; Grote T. M.; Huckabee B. K.; Hendrickson V. S.; Franklin L. C.; Granger E. J.; Karrick, G. L. Org. Process Res. Dev.,1997, 1, 26.
[28] Wang F.; Chen Y.; Pei H.-Y.; Zhang J.; Zhang, L.-X. Chin. J. Org. Chem.,2023, 43, 2826 (in Chinese).
(王锋, 陈钰, 裴鸿艳, 张静, 张立新. 有机化学, 2023, 43, 2826).

新型N-2,3-二氟苯基环丁胺类M4 AChR正向变构调节剂的设计、合成与活性

Design, Synthesis, and Activity of Novel N-2,3-Difluorophenyl Cyclobutylamine M4 AChR Positive Allosteric Modulators

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