兼具誘導神經元生長之膽鹼酯酶抑制劑作為阿茲海默症潛在治療藥物

Abstract

老年相關神經退化性疾病乃由神經元細胞以及神經突觸功能退化，隨著時間推進而惡化，為一種無法醫治且毀滅性的疾病。其中，阿茲海默症(又稱老年失智症)為最常見的神經退化性疾病；在過去這二十年期間，被視為影響全球健康醫療的重要議題。現今，臨床上治療阿茲海默症所使用的藥物主要可分為乙醯膽鹼酶抑制劑(donepezil、 galantamine、rivastigmine)以及NMDA受體拮抗劑(memantine)。然而，上述的藥物只能減輕該疾病所引起的症狀，而無法達到有效治癒的效果。該疾病主要的神經病理標誌物為β-類澱粉樣蛋白，在腦部神經元周圍逐漸堆積形成的斑塊，進而引發一系列的致病性級聯反應，最終造成神經細胞永久性損傷以及失智症狀。因此，近年來的治療策略主要著重於減少β-類澱粉樣蛋白的產生和堆積。然而，在臨床試驗研究上表示這些抗β-類澱粉樣蛋白藥物並未達到治療效果而宣告失敗，主要原因來自於β-類澱粉樣蛋白在腦內的複雜致病機制，因而開發出一創新的治療方法-¬多標靶藥物，進而取代先前的單一標靶藥物。藉由先前實驗室的研究，合成出一多標靶藥物J2326，即有金屬螯合能力、抗金屬誘導性的β-類澱粉樣蛋白堆積以及促進神經滋養活性。在此課題中，我們以J2326、正二十六醇以及rivastigmine的設計概念，設計、合成出新一系列的多標靶藥物，並探討其生物活性。經由結構與活性關係之研究結果證實5-二甲基氨基甲酸酯喹啉-2-氨基辛醇衍生物可做為具有奈米摩爾等級的膽鹼酯酶抑制劑。除此之外，體外生物活性評估結果也顯示其衍生物具有神經滋養活性、減少活性氧化物質生成能力，同時在理化性質上具有適當的溶解度可通過血腦屏障。此多標靶藥物之策略確實證明達到該病症之療效。綜合上述之研究，本論文所開發出來的化合物24a、43c和43d為最有潛力的膽鹼酯酶抑制劑，可進一步做為阿茲海默症之潛在治療藥物。

Age-related neurodegenerative disorders are incurable and debilitating diseases which are marked by a progressive degeneration function of neuronal cells and synapses. Alzheimer’s disease (AD) is considered as the most ordinary neurodegenerative disorder and appears as a serious public health threat over the past two decades. The currently available medication of AD treatment belongs to acetylcholinesterase inhibitors (AChEI, donepezil, galantamine, and rivastigmine) and N-methyl-D-aspartate receptor (NMDA) antagonist (memantine). Regrettably, these anti-AD agents merely provide the symptoms relief or slow down the AD progression. Beta amyloid (Aβ) peptide, a major histopathological hallmark of AD, assembled to form amyloid plaques which consequently initiated a sequence of neuropathological events and caused the degeneration of neuronal process. Hence, reduction of Aβ has considered as the major target against AD recently. However, the anti-Aβ agents were failed to achieve their treatment effects in clinical trials due to the complex pathogenic mechanism of Aβ. Thus, an approach of multi-target directed ligands (MTDLs) has been discovered and prompted the investigation of it into innovative therapeutics over single-target anti-AD drugs. Our previous studies obtained the J2326 as MTDL with specific metal-chelating ability, anti-metal-induced Aβ aggregation, and neurite protection effects. Herein, this dissertation will advance the work of designed, synthesized, and biologically evaluated a novel series compound of multitarget agents by conjugating the pharmacophore of J2326 (8-methoxyquinoline), n-hexacosanol (long aliphatic chain alcohol), and rivastigmine (carbamate). Intensive structure-activity-relationship (SAR) studies of this project were identified the 2-(((8-hydroxyoctyl)amino)methyl)quinolin-5-yl dimethylcarbamate derivatives as potent cholinesterases (ChEs) inhibitors in nano-molar range. Besides, they also have the abilities to induce the neurotrophic activities, reduce reactive oxygen species (ROS) generation, as well as containing an appropriated solubility that could penetrate the blood-brain barrier (BBB). The strategy of MTDL has verified to offer potential therapeutic benefits in AD. Therefore, the compound 24a, 43c, and 43d which prepared in this dissertation with potent inhibitory activity against ChEs might serve as the promising candidates for the development of potential anti-AD drugs.