Zernov Nikita, Melenteva Daria, Ghamaryan Viktor, Makichyan Ani, Hunanyan Lernik, Popugaeva Elena
Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia.
Laboratory of Structural Bioinformatics, Institute of Biomedicine and Pharmacy, Russian-Armenian University, Yerevan 0051, Armenia.
Int J Mol Sci. 2025 May 10;26(10):4591. doi: 10.3390/ijms26104591.
The piperazine derivative N-(2,6-difluorophenyl)-2-(4-phenylpiperazin-1-yl)propanamide (cmp2) has emerged as a potential transient receptor potential cation channel, subfamily C, member 6 (TRPC6) modulator, offering a promising pathway for Alzheimer's disease (AD) therapy. Our recent findings identify cmp2 as a novel compound with synaptoprotective effects in primary hippocampal cultures and effective blood-brain barrier (BBB) penetration. In vivo studies demonstrate that cmp2 (10 mg/kg, intraperitoneally) restores synaptic plasticity deficits in 5xFAD mice. This study further shows cmp2's selectivity towards tetrameric TRPC6 channel in silico. Acute administration of cmp2 is non-toxic, with no indications of chronic toxicity, and Ames testing confirms its lack of mutagenicity. Behavioral assays reveal that cmp2 improves cognitive functions in 5xFAD mice, including increased novel object recognition, better passing of the Morris water maze, and improved fear memory, as well as upregulation of motor function in beam walking tests. These findings suggest that cmp2 holds promise as a candidate for AD treatment.
哌嗪衍生物N-(2,6-二氟苯基)-2-(4-苯基哌嗪-1-基)丙酰胺（cmp2）已成为一种潜在的瞬时受体电位阳离子通道C亚家族成员6（TRPC6）调节剂，为阿尔茨海默病（AD）治疗提供了一条有前景的途径。我们最近的研究结果表明，cmp2是一种在原代海马培养物中具有突触保护作用且能有效穿透血脑屏障（BBB）的新型化合物。体内研究表明，cmp2（10 mg/kg，腹腔注射）可恢复5xFAD小鼠的突触可塑性缺陷。这项研究进一步表明cmp2在计算机模拟中对四聚体TRPC6通道具有选择性。急性给予cmp2无毒，无慢性毒性迹象，艾姆斯试验证实其无致突变性。行为学分析表明，cmp2可改善5xFAD小鼠的认知功能，包括增强新物体识别能力、更好地通过莫里斯水迷宫、改善恐惧记忆，以及在横梁行走试验中上调运动功能。这些发现表明，cmp2有望成为AD治疗的候选药物。
