Departamento de Farmacologia y Terapeutica, Facultad de Medicina, Instituto Teofilo Hernando, Universidad Autonoma de Madrid, C/Arzobispo Morcillo 4, 28029 Madrid, Spain.
J Med Chem. 2010 Jul 22;53(14):5129-43. doi: 10.1021/jm901902w.
1,8-Naphthyridine derivatives related to 17 (ITH4012), a neuroprotective compound reported by our research group, have been synthesized. In general, they have shown better inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) than most tacrine derivatives previously synthesized in our laboratory. The compounds presented an interesting neuroprotective profile in SH-SY5Y neuroblastoma cells stressed with rotenone/oligomycin A. Moreover, compound 14 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate) also caused protection in cells stressed with okadaic acid (OA) or amyloid beta 1-42 peptide (Abeta(1-42)). Interestingly, compound 14 prevented the OA-induced PP2A inhibition, one of the enzymes implicated in tau dephosphorylation. This compound also exhibited neuroprotection against neurotoxicity elicited by oxygen and glucose deprivation in hippocampal slices. Because these stressors caused neuronal damage related to physiopathological hallmarks found in the brain of Alzheimer's disease (AD) patients, we conclude that compound 14 deserves further in vivo studies in AD models to test its therapeutic potential in this disease.
我们研究小组报道了一种神经保护化合物 17（ITH4012），与之相关的 1,8-萘啶衍生物已经合成。总的来说，它们对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的抑制作用比我们实验室以前合成的大多数他克林衍生物都要好。这些化合物在受到鱼藤酮/寡霉素 A 应激的 SH-SY5Y 神经母细胞瘤细胞中呈现出有趣的神经保护特征。此外，化合物 14（乙基 5-氨基-2-甲基-6,7,8,9-四氢苯并[b][1,8]萘啶-3-羧酸乙酯）也能对受到岗田酸（OA）或淀粉样β 1-42 肽（Abeta(1-42)）应激的细胞产生保护作用。有趣的是，化合物 14 可以防止 OA 诱导的蛋白磷酸酶 2A（PP2A）抑制，PP2A 是一种参与 tau 去磷酸化的酶。该化合物还对海马切片中由缺氧和葡萄糖剥夺引起的神经毒性具有神经保护作用。由于这些应激源引起的神经元损伤与阿尔茨海默病（AD）患者大脑中发现的生理病理特征有关，我们得出结论，化合物 14 值得在 AD 模型中进行进一步的体内研究，以测试其在该疾病中的治疗潜力。
