PDF(Pubmed)
Abstract：
The cholinergic system, relying on the neurotransmitter acetylcholine (ACh), plays a significant role in muscle contraction, cognition, and autonomic nervous system regulation. The enzymes acetylcholinesterase, AChE, and butyrylcholinesterase, BChE, responsible for hydrolyzing ACh, can fine-tune the cholinergic system\'s activity and are, therefore, excellent pharmacological targets to address a range of medical conditions. We designed, synthesized, and profiled 14 N-alkyl quaternary quinuclidines as inhibitors of human AChE and BChE and analyzed their impact on cell viability to assess their safety in the context of application as potential therapeutics. Our results showed that all of the 14 tested quinuclidines inhibited both AChE and BChE in the micromolar range (Ki = 0.26 - 156.2 μM). The highest inhibition potency was observed for two bisquaternary derivatives, 7 (1,1\'-(decano)bis(3-hydroxyquinuclidinium bromide)) and 14 (1,1\'-(decano)bis(3-hydroxyiminoquinuclidinium bromide)). The cytotoxic effect within 7-200 μM was observed only for monoquaternary quinuclidine derivatives, especially those with the C12-C16 alkyl chain. Further analysis revealed a time-independent mechanism of action, significant LDH release, and a decrease in the cells\' mitochondrial membrane potential. Taking all results into consideration, we can confirm that a quinuclidine core presents a good scaffold for cholinesterase binding and that two bisquaternary quinuclidine derivatives could be considered as candidates worth further investigations as drugs acting in the cholinergic system. On the other hand, specific cell-related effects probably triggered by the free long alkyl chain in monoquaternary quinuclidine derivatives should not be neglected in future N-alkyl quaternary quinuclidine derivative structure refinements. Such an effect and their potential to interact with other specific targets, as indicated by a pharmacophore model, open up a new perspective for future investigations of these compounds\' scaffold in the treatment of specific conditions and diseases other than cholinergic system-linked disorders.
摘要：
胆碱能系统,依靠神经递质乙酰胆碱（ACh），在肌肉收缩中起着重要作用，认知，和自主神经系统调节。乙酰胆碱酯酶，AChE,丁酰胆碱酯酶,BChE,负责水解ACH，可以微调胆碱能系统的活动，因此,优秀的药理学目标，以解决一系列的医疗条件。我们设计了,合成，并分析了14种N-烷基季奎宁环作为人AChE和BChE的抑制剂，并分析了它们对细胞活力的影响，以评估其在作为潜在治疗剂应用中的安全性。我们的结果表明，所有14个测试的奎宁环都在微摩尔范围内抑制AChE和BChE（Ki=0.26-156.2μM）。两种双季铵盐衍生物的抑制效力最高，7(1,1'-(decano)双(3-羟基喹啉环溴化物))和14(1,1'-(decano)双(3-羟基亚氨基喹啉环溴化物))。7-200μM内的细胞毒性作用仅观察到单季奎宁环衍生物，尤其是具有C12-C16烷基链的那些。进一步的分析揭示了一种与时间无关的作用机制，显著的LDH释放，细胞线粒体膜电位下降。考虑到所有结果，我们可以证实,奎宁环核心为胆碱酯酶结合提供了良好的支架,两种双季胺奎宁环衍生物可被认为是值得进一步研究的候选药物,作为作用于胆碱能系统的药物.另一方面,在未来的N-烷基季奎宁环衍生物结构改进中，不应忽略单季季奎宁环衍生物中自由长烷基链引发的特定细胞相关作用。这种效应及其与其他特定目标相互作用的潜力，如药效团模型所示，为未来研究这些化合物支架在治疗胆碱能系统相关疾病以外的特定条件和疾病中的应用开辟了新的视角。
