基于Sonogashira偶联反应得到的新型α7尼古丁乙酰胆碱受体正向变构调节剂

doi:10.5246/jcps.2022.05.033

中国药学(英文版) ›› 2022, Vol. 31 ›› Issue (5): 374-381.DOI: 10.5246/jcps.2022.05.033

基于Sonogashira偶联反应得到的新型α7尼古丁乙酰胆碱受体正向变构调节剂

谢文军¹^,², 肖浩然¹, 王新童², 黄宗泽¹, 卞希玲², 王克威²^,³^,^*(), 孙崎¹^,^*()

1. 北京大学药学院化学生物学系, 天然药物及仿生药物国家重点实验室, 北京 100191
2. 北京大学药学院分子与细胞药理学系, 北京 100191
3. 青岛大学药学院药理学系, 山东青岛 266021

收稿日期:2021-12-15 修回日期:2022-01-08 接受日期:2022-02-20 出版日期:2022-06-02 发布日期:2022-06-02
通讯作者: 王克威, 孙崎
作者简介:
+ Tel.: +86-10-82805549, E-mail: sunqi@bjmu.edu.cn
+ Tel.: +86-532-82991070, E-mail: wangkw@qdu.edu.cn
基金资助:
National Natural Science Foundation of China awarded to Q. Sun (NSFC, Grant No. 81973169, 21572011) and K.W. Wang (NSFC, Grant No. 81537410), and also from the Ministry of Science and Technology of China to K.W. Wang (Grant No. 2014ZX09507003-006-004).

Sonogashira coupling reaction in the synthesis of novel positive allosteric modulators of α7 nicotinic acetylcholine receptors

Wenjun Xie¹^,², Haoran Xiao¹, Xintong Wang², Zongze Huang¹, Xiling Bian², Kewei Wang²^,³^,^*(), Qi Sun¹^,^*()

1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2 Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
3 Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao 266021, China

Received:2021-12-15 Revised:2022-01-08 Accepted:2022-02-20 Online:2022-06-02 Published:2022-06-02
Contact: Kewei Wang, Qi Sun

摘要/Abstract

摘要：

作者基于课题组先前得到的具有较强α7烟碱型乙酰胆碱受体I型正向变构调节剂活性的先导化合物HZZ-A-11, 运用Sonogashira偶联反应设计并合成了一系列的2-芳氨基-1,3,5-三嗪类衍生物(4a–4g), 所有目标化合物均通过对表达有人源α7乙酰胆碱受体的非洲爪蟾卵使用双电极电压钳技术进行活性评价。在100 μM的乙酰胆碱作用下, 化合物4g显示出比先导化合物HZZ-A-11更高的活性, EC₅₀为1.23 ± 0.41 μM。化合物4g可作为探针分子, 在进一步药理评估中探索其改善精神分裂症和阿尔茨海默氏病的认知缺陷的作用机制。

关键词: 认知缺陷, α7烟碱型乙酰胆碱受体, 正向变构调节剂, Sonogashira偶联反应

Abstract:

A series of 2-arylamino-1,3,5-triazine derivatives (4a–4g), which were designed and synthesized via Sonogashira coupling reaction, were evaluated using two-electrode voltage clamp (TEVC) recordings of human α7 nAChR expressed in Xenopus ooctyes. Compound 4g as a positive allosteric modulator (PAM) showed better efficacy than lead compound 3 (HZZ-A-11) with an EC₅₀ value of 1.23 ± 0.41 μM. Further pharmacological evaluation of compound 4g might lead to the developmental potential for therapy of cognitive deficits commonly shared by neuropsychiatric disorders, such as schizophrenia and Alzheimer’s disease.

Key words: Cognitive deficit, α7 nAChR, Positive allosteric modulators, Sonogashira coupling reaction

Supporting:

谢文军, 肖浩然, 王新童, 黄宗泽, 卞希玲, 王克威, 孙崎. 基于Sonogashira偶联反应得到的新型α7尼古丁乙酰胆碱受体正向变构调节剂[J]. 中国药学(英文版), 2022, 31(5): 374-381.

Wenjun Xie, Haoran Xiao, Xintong Wang, Zongze Huang, Xiling Bian, Kewei Wang, Qi Sun. Sonogashira coupling reaction in the synthesis of novel positive allosteric modulators of α7 nicotinic acetylcholine receptors[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(5): 374-381.

图/表 4

Figure 1. Derivative compounds from compound 1.

Scheme 1. Reagents and conditions: a) Pd(PPh3)2Cl2, dppp, CuTC, CuI, K2CO3 in THF at 95 °C for overnight. b) K2CO3/methanol, 70 °C for 0.5 h. Pd(PPh3)2Cl2 = ditriphenylphosphine palladium dichloride. dppp = [1,3-Bis(diphenylphosphino)propane]nickel (II) chloride. CuTC = copper (I) thiophene-2-carboxylate.

Table 1. AIn vitro activity of compounds 4a?4g in the enhancement of human α7 nAChR currentsa.

Figure 2. Concentration-dependent allosteric activation of α7 current by compound 4g. (a) Representative α7 current evoked by 100 μM ACh in the absence or presence of 4g at various concentrations. Oocytes were pre-incubated with 4g for 2 min, followed by co-application with 100 μM ACh. (b) Relationship between 4g concentration and the response of WT/TSLMFmut α7 nAChR. Oocytes expressing human α7 nAChR were stimulated with 100 μM ACh in the absence or presence of increasing concentrations of 4g. Peak currents were measured and normalized with the amplitude of currents elicited by 100 μM ACh alone. WT: Eenhance (10 μM) = 3230% ± 200%, EC50 = 1.23 ± 0.41 μM, Emax = 3580% ± 480%, Hill coefficient (nH) = 1.11 ± 0.41; TSLMFmut: Eenhance (10 μM) = 905% ± 280%, EC50 = 8.97 ± 4.49 μM, Emax = 1428% ± 424%, Hill coefficient (nH) = 1.65 ± 0.32. TSLMFmut: S223T, A226S, M254L, I281M, V288F.

参考文献 10

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基于Sonogashira偶联反应得到的新型α7尼古丁乙酰胆碱受体正向变构调节剂

Sonogashira coupling reaction in the synthesis of novel positive allosteric modulators of α7 nicotinic acetylcholine receptors

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