AbstractAlzheimer disease (AD) is characterized by progressive loss of memory. Synaptic loss is now the best correlate of cognitive dysfunction in patients with Alzheimer’s disease. Thus, restoration or limitation of synapse loss is a promising strategy for pharmacotherapy of AD. N–N substituted piperazines are widely used chemical compounds for drug interventions to treat different illnesses including CNS diseases such as drug abuse, mental and anxiety disorders.

摘要阿尔茨海默病（AD）的特征是进行性记忆丧失。突触丢失现在是阿尔茨海默病患者认知功能障碍的最佳相关性。因此，恢复或限制突触丢失是AD药物治疗的一种有前途的策略。N–N取代的哌嗪类化合物被广泛用于药物干预，以治疗不同的疾病，包括中枢神经系统疾病，如药物滥用，精神和焦虑症。

Piperazine derivatives are small molecules that are usually well tolerated and cross blood brain barrier (BBB). Thus, disubstituted piperazines are good tools for searching and developing novel disease-modifying drugs. Previously, we have determined the piperazine derivative, 51164, as an activator of TRPC6 in dendritic spines.

哌嗪衍生物是通常耐受性良好并跨越血脑屏障（BBB）的小分子。因此，二取代哌嗪是寻找和开发新型疾病缓解药物的良好工具。以前，我们已经确定哌嗪衍生物51164是树突棘中TRPC6的激活剂。

We have demonstrated synaptoprotective properties of 51164 in AD mouse models. However, 51164 was not able to cross BBB. Within the current study, we identified a novel piperazine derivative, cmp2, that is structurally similar to 51164 but is able to cross BBB. Cmp2 binds central part of monomeric TRPC6 in similar way as hypeforin does.

我们已经证明了51164在AD小鼠模型中的突触保护特性。但是，51164无法跨越BBB。在目前的研究中，我们确定了一种新型哌嗪衍生物cmp2，其结构类似于51164，但能够穿过BBB。Cmp2以与hypeforin类似的方式结合单体TRPC6的中心部分。

Cmp2 selectively activates TRPC6 but not structurally related TRPC3 and TRPC7. Novel piperazine derivative exhibits synaptoprotective properties in culture and slices and penetrates the BBB. In vivo study indicated cmp2 (10 mg/kg I.P.) reversed deficits in synaptic plasticity in the 5xFAD mice. Thus, we suggest that cmp2 is a novel lead compound for drug development.

Cmp2选择性激活TRPC6，但不激活结构相关的TRPC3和TRPC7。新型哌嗪衍生物在培养和切片中表现出突触保护特性，并穿透BBB。体内研究表明，cmp2（10 mg/kg I.P.）逆转了5xFAD小鼠突触可塑性的缺陷。因此，我们建议cmp2是一种用于药物开发的新型先导化合物。

The mechanism of cmp2 action is based on selective TRPC6 stimulation and it is expected to treat synaptic deficiency in hippocampal neurons..

cmp2的作用机制基于选择性TRPC6刺激，有望治疗海马神经元的突触缺陷。。

IntroductionSociety faces an uphill battle in discovering an effective drug therapy for Alzheimer’s disease (AD). Therapy based on the “amyloid-β (Aβ) cascade hypothesis” represents a primary emphasis in AD drug development. However, evidence on anti-amyloid drugs as prospective pharmacological agents for AD has so far emerged mainly from animal experiments and human clinical trials of anti-Aβ drugs have yielded conflicting findings1.

引言社会在发现治疗阿尔茨海默病（AD）的有效药物方面面临着一场艰苦的斗争。基于“淀粉样蛋白-β（Aβ）级联假说”的治疗代表了AD药物开发的主要重点。然而，迄今为止，抗淀粉样蛋白药物作为AD的前瞻性药物的证据主要来自动物实验，抗Aβ药物的人体临床试验产生了相互矛盾的发现1。

Moreover, Aβ oligomers and aggregates are present in healthy aged brains2.The importance of finding new approaches to the treatment AD has been stressed in many studies1. The scholarly discussion of neuronal calcium dysregulation in AD pathology is heated and ongoing3,4,5,6. Targeting neuronal store-operated calcium channels such as the transient receptor potential cation channel, subfamily C, member 6 (TRPC6) appears to be a promising avenue for the development of AD therapy7,8.There is some genetic confirmation of TRPC6 role in AD pathogenesis.

。关于AD病理学中神经元钙调节异常的学术讨论正在激烈进行中3,4,5,6。靶向神经元储存操作的钙通道，例如瞬时受体电位阳离子通道，亚家族C，成员6（TRPC6），似乎是AD治疗发展的有希望的途径7,8。TRPC6在AD发病机制中的作用已有一些遗传学证实。

TRPC6 mRNA levels in the blood cells are specifically reduced in patients with AD and moderate cognitive impairment9. Furthermore, blood TRPC6 expression is related to dementia degree10. It has been found that the knockdown of TRPC6 expression obstructs store-operated calcium entry (nSOCE). The TRPC6 overexpression or the pharmacological activation of them restores nSOCE in hippocampal neurons in AD11,12.

AD和中度认知障碍患者血细胞中TRPC6 mRNA水平特异性降低9。此外，血液TRPC6表达与痴呆程度有关10。已经发现TRPC6表达的敲低阻碍了储存操作的钙进入（nSOCE）。TRPC6过表达或其药理学激活可恢复AD11,12海马神经元中的nSOCE。

TRPC6 overexpression has been shown to rescue mushroom spine loss in presenilin and APP knock-in mouse models of AD11 and also protect neurons from ischemic brain damage13. Mice that overexpress TRPC6 in the brain show improved cognitive function and increased excitatory synapse formation14. Pharmacological activation of TRPC6 protects hippocampal mushroom spines from amyloid toxicity in vitro, e.

TRPC6过表达已被证明可以挽救AD11早老素和APP敲入小鼠模型中蘑菇脊柱的丢失，并保护神经元免受缺血性脑损伤13。在大脑中过度表达TRPC6的小鼠表现出改善的认知功能和增加的兴奋性突触形成14。TRPC6的药理活化在体外保护海马蘑菇棘免受淀粉样蛋白毒性。

Data availability

数据可用性

The datasets used and analyzed during the current study available from the corresponding author, Dr. Popugaeva (lena.popugaeva@gmail.com), on reasonable request.

通讯作者Popugaeva博士提供了当前研究中使用和分析的数据集(lena.popugaeva@gmail.com)。

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Download referencesAcknowledgementsWe thank prof. Dr.Sci. I. Bezprozvanny for the constructive critics of the paper and Dr. Anastasiya Bolshakova for the administrative support. The in silico results of the work were obtained using computational resources of the supercomputing center of Peter the Great Saint-Petersburg Polytechnic University (www.spbstu.ru). The work is partially supported by the “Scientific, methodological and resource support for the implementation of measures to improve the efficiency of the Russian-Armenian (Slavic) and Belarusian-Russian universities in training personnel for the digital economy, including using modern distance technologies” (Additional agreement dated 15 May 2024 № 075-03-2024-004/5) (results depicted on Figs.

下载参考文献致谢我们感谢Dr.Sci教授。一、 Bezprozvanny为论文的建设性批评者，Anastasiya Bolshakova博士为行政支持。这项工作的计算机模拟结果是使用彼得大圣彼德堡理工大学超级计算中心（www.spbstu.ru）的计算资源获得的。这项工作得到了“为实施措施提供科学、方法和资源支持，以提高俄罗斯亚美尼亚（斯拉夫）和白俄罗斯-俄罗斯大学在数字经济培训人员方面的效率，包括使用现代远程技术”（2024年5月15日的附加协议，编号075-03-2024-004/5）（结果如图所示）。

2 and 3). This work is partially funded by Russian Science Foundation Grant № 20-75-10026, dated 15 August 2023, https://rscf.ru/en/project/20-75-10026/ (results depicted on Figs. 4, 5 and 6).Author informationAuthors and AffiliationsLaboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, St.

2和3）。这项工作部分由俄罗斯科学基金会拨款20-75-10026资助，日期为2023年8月15日，https://rscf.ru/en/project/20-75-10026/（结果如图4、5和6所示）。作者信息作者和附属机构分子神经退行性疾病实验室，圣彼得堡圣彼得堡理工大学彼得大帝。

Petersburg, 195251, RussiaNikita Zernov, Daria Melenteva & Elena PopugaevaLaboratory of Structural Bioinformatics, Institute of Biomedicine and Pharmacy, Russian-Armenian University, Yerevan, 0051, ArmeniaViktor Ghamaryan, Ani Makichyan & Lernik HunanyanAuthorsNikita ZernovView author publicationsYou can also search for this author in.

Petersburg，195251，RussiaNikita Zernov，Daria Melenteva＆Elena Popugaeva俄罗斯亚美尼亚大学生物医学与药学研究所结构生物信息学实验室，埃里温，0051，亚美尼亚人Ghamaryan，Ani Makichyan＆Lernik HunanyanAuthorsNikita Zernoview作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarViktor GhamaryanView author publicationsYou can also search for this author in

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PubMed Google ScholarDaria MelentevaView author publicationsYou can also search for this author in

PubMed Google ScholarDaria MelentevaView作者出版物您也可以在

PubMed Google ScholarAni MakichyanView author publicationsYou can also search for this author in

PubMed Google ScholarAni MakichyanView作者出版物您也可以在

PubMed Google ScholarLernik HunanyanView author publicationsYou can also search for this author in

PubMed Google ScholarLernik HunanyanView作者出版物您也可以在

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PubMed Google ScholarContributionsE.P., L.H., N.Z., V.G., D.M. and A.M. wrote and edited the manuscript; N.Z. and D.M. conducted in vitro experiments; N.Z. conducted in vivo experiments. V.G. and A.M. conducted the in silico experiments. All authors have read and agreed to the published version of the manuscript.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献。P、 ，L.H.，N.Z.，V.G.，D.M.和A.M.撰写并编辑了手稿；N、 Z.和D.M.进行了体外实验；N、 Z.进行体内实验。五、 G.和A.M.进行了计算机模拟实验。所有作者均已阅读并同意稿件的发布版本。对应作者对应。

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Reprints and permissionsAbout this articleCite this articleZernov, N., Ghamaryan, V., Melenteva, D. et al. Discovery of a novel piperazine derivative, cmp2: a selective TRPC6 activator suitable for treatment of synaptic deficiency in Alzheimer’s disease hippocampal neurons.

转载和许可本文引用本文Zernov，N.，Ghamaryan，V.，Melenteva，D。等人发现了一种新型哌嗪衍生物cmp2：一种适用于治疗阿尔茨海默病海马神经元突触缺陷的选择性TRPC6激活剂。

Sci Rep 14, 23512 (2024). https://doi.org/10.1038/s41598-024-73849-zDownload citationReceived: 24 June 2024Accepted: 20 September 2024Published: 09 October 2024DOI: https://doi.org/10.1038/s41598-024-73849-zShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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KeywordsTRPC6Alzheimer’s diseasePiperazine

关键词TRPC6Alzheimer病哌嗪

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