Screening of Transient Receptor Potential Canonical Channel Activators Identifies Novel Neurotrophic Piperazine Compounds
Screening of Transient Receptor Potential Canonical Channel Activators Identifies Novel Neurotrophic Piperazine Compounds
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DOI：
10.1124/mol.115.102863
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发表时间：
2016-03
影响因子：
3.6
通讯作者：
Seishiro Sawamura;M. Hatano;Yoshinori Takada;K. Hino;T. Kawamura;J. Tanikawa;H. Nakagawa;Hideharu Hase;Akito Nakao;Mitsuru Hirano;Rachapun Rotrattanadumrong;Shigeki Kiyonaka;M. Mori;M. Nishida;Yaopeng Hu;R. Inoue;R. Nagata;Y. Mori
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文献类型：
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作者：
Seishiro Sawamura;M. Hatano;Yoshinori Takada;K. Hino;T. Kawamura;J. Tanikawa;H. Nakagawa;Hideharu Hase;Akito Nakao;Mitsuru Hirano;Rachapun Rotrattanadumrong;Shigeki Kiyonaka;M. Mori;M. Nishida;Yaopeng Hu;R. Inoue;R. Nagata;Y. Mori
瞬时受体潜能型(TRPC)蛋白在与磷脂酶C偶联的代谢性受体的刺激下形成钙离子通透性阳离子通道。在TRPC亚家族中，由二酰甘油(DAG)直接激活的TRPC3和TRPC6通道在脑源性神经营养因子(BDNF)信号转导中发挥重要作用，促进神经元的发育和存活。在各种疾病模型中，BDNF可以恢复神经功能障碍，但其治疗潜力因其较差的药代动力学特征而受到限制。通过TRPC3和TRPC6诱导BDNF样活性的小分子设计框架的阐明，为克服这一限制奠定了坚实的基础。通过文库筛选，我们发现了一组哌嗪类化合物，它们激活了DAG激活的TRPC3/TRPC6/TRPC7通道。化合物[4-(5-chloro-2-methylphenyl)piperazin-1-yl](3-fluorophenyl)methanone(PPZ1)和2-[4-(2，3-dimethylphenyl)piperazin-1-yl]-N-(2-ethoxyphenyl)acetamide(PPZ2)以剂量依赖的方式激活重组的TRPC3/TRPC6/TRPC7通道，但不激活其他TRPC。PPZ2激活兔门静脉平滑肌细胞天然TRPC6样通道。PPZ2还可引起培养的大鼠中枢神经元阳离子电流和钙内流。值得注意的是，这两种化合物都能诱导BDNF样神经突起生长和神经保护作用，但这一作用可被TRPC3/TRPC6/TRPC7抑制或抑制。钙信号通路的抑制剂，除钙调神经磷酸酶外，可抑制PPZ化合物诱导的轴突生长。PPZ2增加了钙离子依赖的转录因子cAMP反应元件结合蛋白的激活。这些发现表明，激活DAG激活的TRPC通道所介导的钙信号是PPZ化合物的神经营养作用的基础。因此，哌嗪衍生的DAG激活的TRPC通道激活剂为未来开发一类新的合成神经营养药物提供了重要的见解。
Transient receptor potential canonical (TRPC) proteins form Ca2+-permeable cation channels activated upon stimulation of metabotropic receptors coupled to phospholipase C. Among the TRPC subfamily, TRPC3 and TRPC6 channels activated directly by diacylglycerol (DAG) play important roles in brain-derived neurotrophic factor (BDNF) signaling, promoting neuronal development and survival. In various disease models, BDNF restores neurologic deficits, but its therapeutic potential is limited by its poor pharmacokinetic profile. Elucidation of a framework for designing small molecules, which elicit BDNF-like activity via TRPC3 and TRPC6, establishes a solid basis to overcome this limitation. We discovered, through library screening, a group of piperazine-derived compounds that activate DAG-activated TRPC3/TRPC6/TRPC7 channels. The compounds [4-(5-chloro-2-methylphenyl)piperazin-1-yl](3-fluorophenyl)methanone (PPZ1) and 2-[4-(2,3-dimethylphenyl)piperazin-1-yl]-N-(2-ethoxyphenyl)acetamide (PPZ2) activated, in a dose-dependent manner, recombinant TRPC3/TRPC6/TRPC7 channels, but not other TRPCs, in human embryonic kidney cells. PPZ2 activated native TRPC6-like channels in smooth muscle cells isolated from rabbit portal vein. Also, PPZ2 evoked cation currents and Ca2+ influx in rat cultured central neurons. Strikingly, both compounds induced BDNF-like neurite growth and neuroprotection, which were abolished by a knockdown or inhibition of TRPC3/TRPC6/TRPC7 in cultured neurons. Inhibitors of Ca2+ signaling pathways, except calcineurin, impaired neurite outgrowth promotion induced by PPZ compounds. PPZ2 increased activation of the Ca2+-dependent transcription factor, cAMP response element–binding protein. These findings suggest that Ca2+ signaling mediated by activation of DAG-activated TRPC channels underlies neurotrophic effects of PPZ compounds. Thus, piperazine-derived activators of DAG-activated TRPC channels provide important insights for future development of a new class of synthetic neurotrophic drugs.