Sanz Elisenda, Romera Manuel, Bellik Lydia, Marco J I, Unzeta Mercedes
Departament de Bioquimca i Biologia Molecular, Facultad de Medicina, Institut de Neurociencies, Universitat Autónoma de Barcelona, Campus Universitari de Bellaterra, Barcelona, Spain.
Med Sci Monit. 2004 Dec;10(12):BR477-84.
The neuroprotective effect of N-(2-propynyl)2-(5-benzyloxy-indol)methylamine (PF 9601N), a novel MAO B inhibitor, and its metabolite FA 72 on the human neuroblastoma SHSY5Y cell line lesioned with (300 microM) dopamine was assessed and compared with that of 1-deprenyl assayed at identical experimental conditions.
MATERIAL/METHODS: Using this experimental model, PF 961N showed a neuroprotective effect in a dose-dependent manner, and at a concentration of 10 pM a 20% recovery of cell viability was observed. However, the metabolite FA72 assayed under the same experimental conditions showed an increase in cell viability of nearly 50%. In the case of l-deprenyl, a concentration of 100 microM was necessary to recover only 10% of cell viability.
This neuroprotective effect could be explained in terms of the antioxidant capacity of PF 9601N. In this context, the antioxidant capacities of the novel series of MAO inhibitors, PF 9601N and its analogues, were evaluated by their inhibition of the auto-oxidation of dopamine to melanin and by the dichlorofluorescein and 2-deoxyribose methods.
All of these compounds have the basic structure of an indole ring in common, but show different substituents at different positions in it. The corresponding structure-activity relationship studies allowed us to conclude that the presence of a benzyloxy group, or a hydroxy or methoxy group, at position 5 of the indol ring enhanced these antioxidant characteristics, presenting a decreasing order of antioxidant activity of the primary > secondary > tertiary amines. The antioxidant properties of PF 9601 N would explain its neuroprotective effect observed in SHSY5Y cells lesioned with dopamine.
评估了新型单胺氧化酶B（MAO B）抑制剂N-（2-丙炔基）-2-（5-苄氧基-吲哚）甲胺（PF 9601N）及其代谢产物FA 72对经（300微摩尔）多巴胺损伤的人神经母细胞瘤SHSY5Y细胞系的神经保护作用，并在相同实验条件下与司来吉兰的作用进行比较。
材料/方法：在该实验模型中，PF 961N呈剂量依赖性地显示出神经保护作用，在浓度为10皮摩尔时观察到细胞活力恢复了20%。然而，在相同实验条件下检测的代谢产物FA72显示细胞活力增加了近50%。对于司来吉兰，需要100微摩尔的浓度才能仅恢复10%的细胞活力。
这种神经保护作用可以用PF 9601N的抗氧化能力来解释。在此背景下，通过抑制多巴胺自氧化为黑色素以及采用二氯荧光素和2-脱氧核糖方法，评估了新型MAO抑制剂系列PF 9601N及其类似物的抗氧化能力。
所有这些化合物都具有共同的吲哚环基本结构，但在其上不同位置显示出不同的取代基。相应的构效关系研究使我们得出结论，吲哚环5位上存在苄氧基、羟基或甲氧基可增强这些抗氧化特性，呈现出伯胺>仲胺>叔胺的抗氧化活性递减顺序。PF 9601 N的抗氧化特性可以解释其在多巴胺损伤的SHSY5Y细胞中观察到的神经保护作用。
