Normandie Univ, UNICAEN, CERMN, 14000 Caen, France.
Univ. Montpellier, CNRS, INSERM, IGF, 34090 Montpellier, France.
Molecules. 2019 Jul 31;24(15):2786. doi: 10.3390/molecules24152786.
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.
阿尔茨海默病（AD）是一种多因素神经退行性疾病，目前仍知之甚少。目前用于治疗 AD 的药物主要是乙酰胆碱酯酶抑制剂（AChEI），被认为临床效果不足，并导致有害的副作用。然而，通过发现 AChE 在 AD 发病机制中发挥的伴侣蛋白作用，AChE 目前重新引起了人们的兴趣。但是，AChE 也可以作为多效前药的激活蛋白。事实上，用能够与酶共价结合并同时在大脑中释放活性代谢物的穿透性脑设计氨基甲酸酯抑制中枢 AChE，可以构成一种更有效的临床方法，此外，不太可能引起外周副作用。我们旨在通过对靶向 5-HT 受体和 AChE 的多效前药进行体外和体内研究，为这种新途径铺平道路，以显示与胆碱能神经传递的持续恢复相关的神经保护活性，而没有与经典 AChEI 相关的常见外周副作用。这种多效活性可以为 AD 患者带来有效、相对安全、对症和疾病修饰的治疗益处。
