Fatty Acid Amide Hydrolase (FAAH), Acetylcholinesterase (AChE), and Butyrylcholinesterase (BuChE): Networked Targets for the Development of Carbamates as Potential Anti-Alzheimer’s Disease Agents

The modulation of the endocannabinoid
system is emerging as a viable
avenue for the treatment of neurodegeneration, being involved in neuroprotective
and anti-inflammatory processes. In particular, indirectly enhancing
endocannabinoid signaling to therapeutic levels through FAAH inhibition
might be beneficial for neurodegenerative disorders such as Alzheimer’s
disease, effectively preventing or slowing the progression of the
disease. Hence, in the search for a more effective treatment for Alzheimer’s
disease, in this paper, the multitarget-directed ligand paradigm was
applied to the design of carbamates able to simultaneously target
the recently proposed endocannabinoid system and the classic cholinesterase
system, and achieve effective dual FAAH/cholinesterase inhibitors.
Among the two series of synthesized compounds, while some derivatives
proved to be extremely potent on a single target, compounds 9 and 19 were identified as effective dual FAAH/ChE
inhibitors, with well-balanced nanomolar activities. Thus, 9 and 19 might be considered as new promising candidates
for Alzheimer’s disease treatment.

内源性大麻素系统（endocannabinoid system）的调控正逐渐成为治疗神经退行性疾病的可行途径，该系统参与神经保护与抗炎过程。具体而言，通过脂肪酸酰胺水解酶（fatty acid amide hydrolase, FAAH）抑制作用，将内源性大麻素信号通路间接增强至治疗水平，或可对阿尔茨海默病等神经退行性疾病产生益处，有效阻断或延缓疾病进程。因此，为探寻阿尔茨海默病更有效的治疗手段，本文采用多靶点配体（multitarget-directed ligand）设计范式，开发可同时靶向新近提出的内源性大麻素系统与经典胆碱酯酶（cholinesterase, ChE）系统的氨基甲酸酯类化合物，以获得高效的FAAH/胆碱酯酶双重抑制剂。在所合成的两类化合物中，尽管部分衍生物仅对单一靶点展现出极强活性，但化合物9与19被证实为兼具活性的双重抑制剂，二者均具备平衡良好的纳摩尔级活性。因此，化合物9与19可被视为治疗阿尔茨海默病的新型候选药物，具有良好的开发前景。