Background: There is currently no drug that slows the process of neurodegeneration or alleviates the cognitive and depressive symptoms in patients with Alzheimer’s disease. Due to the increasing number of Alzheimer’s patients, there is an urgent need to develop novel drugs with neuroprotective, procognitive, and antidepressant properties.

Objective: The aim of this study was to design, synthesize, and evaluate novel aminoalkanamides with serotonin 5-HT_1A/5-HT₇ receptor affinity and phosphodiesterase (PDE) inhibitory activity as a new approach to combat neurodegeneration and symptoms of Alzheimer’s disease.

Methods: The newly designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their receptor affinity, functional profile, enzyme inhibition, and ADME properties. The neuroprotective effect against H₂O₂-induced increase of reactive oxygen species level was tested in SH-SY5Y cells. The novel object recognition and forced swimming tests were used to evaluate the procognitive and antidepressant activity, respectively.

Results: Synthesized aminoalkanamides were characterized as potent 5-HT_1A receptor antagonists with additional 5-HT7 receptor antagonistic properties and PDE4B inhibitory activity. Selected compound 15 showed neuroprotective, procognitive, and antidepressant properties. In addition, compound 15 revealed suitable ADME properties expressed as good membrane permeability and high metabolic stability.

Conclusion: This study revealed a new class of compounds that may be useful in the search for an effective drug in the alleviation of neurodegeneration and symptoms of Alzheimer’s disease.

背景：目前没有药物可以减缓阿尔茨海默病患者的神经变性过程或减轻认知和抑郁症状。由于阿尔茨海默病患者的数量不断增加，迫切需要开发具有神经保护、促认知和抗抑郁特性的新型药物。

目的：本研究的目的是设计、合成和评估具有 5-羟色胺 5-HT _1A /5-HT ₇受体亲和力和磷酸二酯酶 (PDE) 抑制活性的新型氨基链烷酰胺，作为对抗神经变性和阿尔茨海默病症状的新方法。

方法：使用经典的有机化学方法合成新设计的化合物，并在体外测试其受体亲和力、功能特征、酶抑制和 ADME 特性。在SH-SY5Y细胞中测试了针对H ₂ O ₂诱导的活性氧水平增加的神经保护作用。新的物体识别和强迫游泳测试分别用于评估预测和抗抑郁活性。

结果：合成的氨基烷酰胺被表征为有效的 5-HT _1A受体拮抗剂，具有额外的 5-HT7 受体拮抗特性和 PDE4B 抑制活性。选定的化合物 15 显示出神经保护、促认知和抗抑郁特性。此外，化合物 15 显示出合适的 ADME 特性，表现为良好的膜渗透性和高代谢稳定性。

结论：这项研究揭示了一类新的化合物，可用于寻找缓解神经变性和阿尔茨海默病症状的有效药物。