Matošević Ana, Radman Kastelic Andreja, Mikelić Ana, Zandona Antonio, Katalinić Maja, Primožič Ines, Bosak Anita, Hrenar Tomica
Institute for Medical Research and Occupational Health, Ksaverska Cesta 2, HR-10 000 Zagreb, Croatia.
Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102A, HR-10 000 Zagreb, Croatia.
Pharmaceutics. 2021 Mar 20;13(3):420. doi: 10.3390/pharmaceutics13030420.
The treatment of central nervous system (CNS) diseases related to the decrease of neurotransmitter acetylcholine in neurons is based on compounds that prevent or disrupt the action of acetylcholinesterase and butyrylcholinesterase. A series of thirteen quinuclidine carbamates were designed using quinuclidine as the structural base and a carbamate group to ensure the covalent binding to the cholinesterase, which were synthesized and tested as potential human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The synthesized compounds differed in the substituents on the amino and carbamoyl parts of the molecule. All of the prepared carbamates displayed a time-dependent inhibition with overall inhibition rate constants in the 10 M min range. None of the compounds showed pronounced selectivity for any of the cholinesterases. The in silico determined ability of compounds to cross the blood-brain barrier (BBB) revealed that six compounds should be able to pass the BBB by passive transport. In addition, the compounds did not show toxicity toward cells that represented the main models of individual organs. By machine learning, the most optimal regression models for the prediction of bioactivity were established and validated. Models for AChE and BChE described 89 and 90% of the total variations among the data, respectively. These models facilitated the prediction and design of new and more potent inhibitors. Altogether, our study confirmed that quinuclidinium carbamates are promising candidates for further development as CNS-active drugs, particularly for Alzheimer's disease treatment.
针对与神经元中神经递质乙酰胆碱减少相关的中枢神经系统（CNS）疾病的治疗，是基于能够预防或破坏乙酰胆碱酯酶和丁酰胆碱酯酶作用的化合物。以奎宁环为结构基础并引入氨基甲酸酯基团设计了一系列十三种奎宁环氨基甲酸酯，以确保与胆碱酯酶的共价结合，这些化合物被合成并作为潜在的人类乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）抑制剂进行测试。合成的化合物在分子的氨基和氨基甲酰部分的取代基上有所不同。所有制备的氨基甲酸酯均表现出时间依赖性抑制，总体抑制速率常数在10 M min范围内。没有一种化合物对任何一种胆碱酯酶表现出明显的选择性。通过计算机模拟确定的化合物穿越血脑屏障（BBB）的能力表明，有六种化合物应该能够通过被动转运穿过血脑屏障。此外，这些化合物对代表各个器官主要模型的细胞没有显示出毒性。通过机器学习，建立并验证了用于预测生物活性的最优回归模型。针对AChE和BChE的模型分别描述了数据中总变异的89%和90%。这些模型有助于预测和设计新的、更有效的抑制剂。总之，我们的研究证实，奎宁环氨基甲酸酯作为中枢神经系统活性药物，特别是用于治疗阿尔茨海默病，是有前途的进一步开发候选药物。
