Cholinergic neurons are ubiquitous and involved in various higher brain functions including learning and memory. Patients with Alzheimer's disease exhibit significant dysfunction and loss of cholinergic neurons. Meanwhile, such cholinergic deficits can be potentially relieved pharmacologically by increasing acetylcholine. Acetylcholinesterase (AChE) inhibitors have been used to improve cholinergic transmission in the brain for two decades and have proven effective for alleviating symptoms in the early stages of Alzheimer's disease. Therefore, the search for AChE inhibitors for drug development is ongoing. The enzymatic pocket of AChE has long been the target of several drug designs over the last two decades. The peripheral and catalytic sites of AChE are simultaneously bound by several dimeric molecules, enabling more-efficient inhibition. Here, we used 6-chlorotacrine and the tetrahydroquinolone moiety of huperzine A to design and synthesize a series of heterodimers that inhibit AChE at nanomolar potency. Specifically, compound 7b inhibits AChE with an IC₅₀ < 1 nM and spares butyrylcholinesterase. Administration of 7b to mouse brain slices restores synaptic activity impaired by pirenzepine, a muscarinic M1-selective antagonist. Moreover, oral administration of 7b to C57BL/6 mice enhances hippocampal long-term potentiation in a dose-dependent manner and is detectable in the brain tissue. All these data supported that 7b is a potential cognitive enhancer and is worth for further exploration.

胆碱能神经元无处不在，并参与各种高级大脑功能，包括学习和记忆。阿尔茨海默病患者表现出明显的功能障碍和胆碱能神经元丢失。同时，通过增加乙酰胆碱可以潜在地缓解这种胆碱能缺陷。乙酰胆碱酯酶 (AChE) 抑制剂已被用于改善大脑中的胆碱能传递 20 年，并已证明可有效缓解阿尔茨海默病早期症状。因此，正在寻找用于药物开发的 AChE 抑制剂。在过去的二十年里，AChE 的酶袋一直是几种药物设计的目标。AChE 的外围和催化位点同时被几个二聚体分子结合，从而实现更有效的抑制。在这里，我们使用 6-chlorotacrine 和石杉碱 A 的四氢喹诺酮部分来设计和合成一系列以纳摩尔效价抑制 AChE 的异二聚体。具体来说，复合图 7b以 IC ₅₀ < 1 nM抑制 AChE 并节省丁酰胆碱酯酶。向小鼠脑切片施用7b可恢复因哌仑西平（一种毒蕈碱 M1 选择性拮抗剂）受损的突触活动。此外，C57BL/6 小鼠口服7b以剂量依赖性方式增强海马的长期增强作用，并且在脑组织中可检测到。所有这些数据都支持7b是一种潜在的认知增强剂，值得进一步探索。