Synthesis, Pharmacological Assessment, and Molecular Modeling of Acetylcholinesterase/Butyrylcholinesterase Inhibitors: Effect against Amyloid-尾-Induced Neurotoxicity

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• 作者：Daniel Silva ; Mourad Chioua ; Abdelouahid Samadi ; Paula Agostinho ; Pedro Gar莽茫o ; Roc铆o Lajar铆n-Cuesta ; Cristobal de los R铆os ; Isabel Iriepa ; Ignacio Moraleda ; Laura Gonzalez-Lafuente ; Eduarda Mendes ; Concepci贸n P茅rez ; Mar铆a Isabel Rodr铆guez-Franco ; Jos茅 Marco-Contelles ; M. Carmo Carreiras
• 刊名：ACS Chemical Neuroscience
• 出版年：2013
• 出版时间：April 17, 2013
• 年：2013
• 卷：4
• 期：4
• 页码：547-565
• 全文大小：952K
• 年卷期：v.4,no.4(April 17, 2013)
• ISSN：1948-7193

文摘

The synthesis, molecular modeling, and pharmacological analysis of phenoxyalkylamino-4-phenylnicotinates (2鈥?b>7), phenoxyalkoxybenzylidenemalononitriles (12, 13), pyridonepezils (14鈥?b>18), and quinolinodonepezils (19鈥?b>21) are described. Pyridonepezils 15鈥?b>18 were found to be selective and moderately potent regarding the inhibition of hAChE, whereas quinolinodonepezils 19鈥?b>21 were found to be poor inhibitors of hAChE. The most potent and selective hAChE inhibitor was ethyl 6-(4-(1-benzylpiperidin-4-yl)butylamino)-5-cyano-2-methyl-4-phenylnicotinate (18) [IC₅₀ (hAChE) = 0.25 卤 0.02 渭M]. Pyridonepezils 15鈥?b>18 and quinolinodonepezils 20鈥?b>21 are more potent selective inhibitors of EeAChE than hAChE. The most potent and selective EeAChE inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) [IC₅₀ (EeAChE) = 0.0167 卤 0.0002 渭M], which exhibits the same inhibitory potency as donepezil against hAChE. Compounds 2, 7, 13, 17, 18, 35, and 36 significantly prevented the decrease in cell viability caused by A尾_1鈥?2. All compounds were effective in preventing the enhancement of AChE activity induced by A尾_1鈥?2. Compounds 2鈥?b>7 caused a significant reduction whereas pyridonepezils 17 and 18, and compound 16 also showed some activity_. The pyrazolo[3,4-b]quinolines 36 and 38 also prevented the upregulation of AChE induced by A尾_1鈥?2. Compounds 2, 7, 12, 13, 17, 18, and 36 may act as antagonists of voltage sensitive calcium channels, since they significantly prevented the Ca²⁺ influx evoked by KCl depolarization. Docking studies show that compounds 16 and 18 adopted different orientations and conformations inside the active-site gorges of hAChE and hBuChE. The structural and energetic features of the 16-AChE and 18-AChE complexes compared to the 16-BuChE and 18-BuChE complexes account for a higher affinity of the ligand toward AChE. The present data indicate that compounds 2, 7, 17, 18, and 36 may represent attractive multipotent molecules for the potential treatment of Alzheimer鈥檚 disease.

Keywords:

Pyridonepezils; quinolinodonepezils; AChE/BuChE inhibitors; A尾 peptide; neuroprotection; Ca²⁺ dyshomeostasis; Alzheimer鈥檚 disease