The known neuroprotective actions of melatonin could be due to its antioxidant or radical scavenging activity, or they could be due to specific interactions of the indole with its receptors. A study of structure-activity relationships may provide useful information when a validated macromolecular target has not been (or is not) identified. A set of indole derivatives, with changes in the 5-methoxy and acylamino groups, the side chain position and the lipophilic/hydrophilic balance, were selected and tested for their in vitro antioxidant potency in the ABTS (2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid disodium salt) and thiobarbituric acid reactive substances (TBARS) assays and for their cytoprotective activity against kainate excitotoxicity on cerebellar cell cultures. No quantitative model was able to relate the potencies obtained in the two antioxidant assays, probably because they are related to different physico-chemical properties. However, the lipophilicity of the compounds and the antioxidant potency in the TBARS assay were linearly correlated. This may be due to improved access to the lipidic substrate, where the antioxidant action occurs. In the cytoprotection assay, most compounds showed potencies comparable with or lower than melatonin. An exception was N-[2-(5-methoxy-1H-indol-2-yl)ethyl]acetamide (12), yielding, at 50 microM, percentages of cell vitality higher than 75%, while melatonin EC50 was 333 microM. No correlation was observed between cytoprotective and antioxidant potencies, nor with MT1 or MT(2) receptor affinity. Compound 12 is a low-affinity antagonist at melatonin membrane receptors, and one of the most potent compounds in the antioxidant assays; its cytoprotective potency and the absence of agonist activity at melatonin membrane receptors make it a valid candidate for further investigations.

中文翻译：

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褪黑素的基于吲哚的类似物：体外抗氧化剂和细胞保护活性。

褪黑激素的已知神经保护作用可能是由于其抗氧化剂或自由基清除活性，或者可能是由于吲哚与其受体之间的特定相互作用。当尚未确认（或未确认）经过验证的大分子靶标时，对结构-活性关系的研究可能会提供有用的信息。选择了一组具有5-甲氧基和酰基氨基基团，侧链位置和亲脂/亲水平衡变化的吲哚衍生物，并测试了它们在ABTS中的体外抗氧化能力（2,2'-azinobis（3 -乙基苯并噻唑啉-6-磺酸二钠盐）和硫代巴比妥酸反应性物质（TBARS）测定及其对小脑细胞培养物抗红藻氨酸兴奋性毒性的细胞保护活性。没有定量模型能够关联在两种抗氧化剂测定中获得的效力，可能是因为它们与不同的理化性质有关。然而，在TBARS测定中，化合物的亲脂性和抗氧化能力是线性相关的。这可能是由于获得抗氧化剂作用的脂质底物获得了更好的进入。在细胞保护测定中，大多数化合物显示出与褪黑激素相当或更低的效力。N- [2-（5-甲氧基-1H-吲哚-2-基）乙基]乙酰胺（12）是一个例外，在50 microM时产生的细胞活力百分比高于75％，而褪黑激素EC50为333 microM。没有相关性被观察到之间的细胞保护和抗氧化剂的效力，也没有与MT1或MT（2）受体亲和力。化合物12是褪黑激素膜受体的低亲和力拮抗剂，和抗氧化剂测定中最有效的化合物之一；它的细胞保护能力以及对褪黑激素膜受体的激动剂活性不足，使其成为进一步研究的有效候选者。