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

doi:10.6023/cjoc202510015

摘要/Abstract

以VU6000918为先导化合物, 采用Schrödinger平台的Glide对接模块对所设计的目标化合物与M4受体蛋白的变构位点均进行了分子对接和打分评估, 设计并合成了27个N-2,3-二氟苯基环丁胺类化合物V1~V27. 采用FLIPR (Fluorescence imaging plate reader)荧光检测技术研究化合物对M4细胞的活性, 研究结果显示, 部分化合物具有显著的M4受体细胞活性, 其中化合物V1 (EC₅₀=0.636 μmol/L)、V8 (EC₅₀=0.482 μmol/L)、V10 (EC₅₀=0.508 μmol/L)和V13 (EC₅₀=0.621 μmol/L)对M4受体细胞的活性高于阳性对照或与之相当. 构效关系研究发现, 化合物中含喹啉环时表现出较高的细胞活性, 尤其是在喹啉环的4位引入甲基时, 化合物较其它取代基化合物活性更高, 表明甲基的引入可以显著提高化合物的活性, 值得进一步研究. 分子对接结果表明, 该类化合物能够有效地与M4受体的变构位点发生结合, 从而发挥其潜在的药理作用. 本研究结果对M4 AChR正向变构调节剂的新药分子设计具有一定的借鉴意义.

关键词: 分子对接, M4正向变构调节剂, N-2,3-二氟苯基环丁胺, 合成, 活性

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 imaging plate reader) fluorescence detection technology. The results showed that some target compounds exhibited significant activities on M4 receptor cells. Among them, compounds V1 (EC₅₀=0.636 μmol/L), V8 (EC₅₀=0.482 μmol/L), V10 (EC₅₀=0.508 μmol/L), and V13 (EC₅₀=0.621 μmol/L) 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, 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

引用此文

刘敏, 陈毅昆, 田峦鸢, 周海峰, 周皓, 刘祈星. 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[J]. 有机化学, 2026, 46(5): 2138-2148.

Min Liu, Yikun Chen, Luanyuan Tian, Haifeng Zhou, Hao Zhou, Qixing Liu. Design, Synthesis, and Activity of Novel N-2,3-Difluorophenyl Cyclobutylamine M4 AChR Positive Allosteric Modulators[J]. Chinese Journal of Organic Chemistry, 2026, 46(5): 2138-2148.

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Compd.	Docking score/(kJ∙mol^－1)	Compd.	Docking score/(kJ∙mol^－1)	Compd.	Docking score/(kJ∙mol^－1)
V1	－31.9	V11	－29.0	V21	－27.4
V2	－32.0	V12	－24.6	V22	－27.9
V3	－32.0	V13	－33.4	V23	－33.0
V4	－31.9	V14	－30.9	V24	－35.2
V5	－29.9	V15	－37.0	V25	－34.5
V6	－31.4	V16	－34.5	V26	－26.4
V7	－29.7	V17	－28.3	V27	－30.0
V8	－31.7	V18	－34.7	VU6000918	－22.7
V9	－24.3	V19	－28.5	VU0467154	－25.6
V10	－29.8	V20	－32.1

Compd.	Docking score/(kJ∙mol^－1)	Compd.	Docking score/(kJ∙mol^－1)	Compd.	Docking score/(kJ∙mol^－1)
V1	－31.9	V11	－29.0	V21	－27.4
V2	－32.0	V12	－24.6	V22	－27.9
V3	－32.0	V13	－33.4	V23	－33.0
V4	－31.9	V14	－30.9	V24	－35.2
V5	－29.9	V15	－37.0	V25	－34.5
V6	－31.4	V16	－34.5	V26	－26.4
V7	－29.7	V17	－28.3	V27	－30.0
V8	－31.7	V18	－34.7	VU6000918	－22.7
V9	－24.3	V19	－28.5	VU0467154	－25.6
V10	－29.8	V20	－32.1

Compd.	EC₅₀/(μmol∙L^－1)	Compd.	EC₅₀/(μmol∙L^－1)	Compd.	EC₅₀/(μmol∙L^－1)
V1	0.636±0.02	V11	2.840±0.02	V21	>30
V2	2.652±0.02	V12	1.450±0.02	V22	>30
V3	3.033±0.02	V13	0.621±0.02	V23	>30
V4	>30	V14	2.376±0.02	V24	>30
V5	1.888±0.02	V15	1.999±0.02	V25	>30
V6	1.094±0.02	V16	>30	V26	>30
V7	0.979±0.02	V17	>30	V27	13.930±0.02
V8	0.482±0.02	V18	>30	VU0467154	0.636±0.02
V9	4.000±0.02	V19	>30	VU6000918	0.120±0.02
V10	0.508±0.02	V20	>30

Compd.	EC₅₀/(μmol∙L^－1)	Compd.	EC₅₀/(μmol∙L^－1)	Compd.	EC₅₀/(μmol∙L^－1)
V1	0.636±0.02	V11	2.840±0.02	V21	>30
V2	2.652±0.02	V12	1.450±0.02	V22	>30
V3	3.033±0.02	V13	0.621±0.02	V23	>30
V4	>30	V14	2.376±0.02	V24	>30
V5	1.888±0.02	V15	1.999±0.02	V25	>30
V6	1.094±0.02	V16	>30	V26	>30
V7	0.979±0.02	V17	>30	V27	13.930±0.02
V8	0.482±0.02	V18	>30	VU0467154	0.636±0.02
V9	4.000±0.02	V19	>30	VU6000918	0.120±0.02
V10	0.508±0.02	V20	>30