Methylene blue (MB) possesses diverse medical applications. Among these, MB presents with antidepressant-like effects in animals and has shown promise in clinical trials for the treatment of mood disorders. As an antidepressant, MB may act via various mechanisms which include modulation of the nitric oxide cyclic guanosine monophosphate (NO-cGMP) cascade, enhancement of mitochondrial respiration and antioxidant effects. MB is also, however, a high potency inhibitor of monoamine oxidase (MAO) A, which most likely contributes to its antidepressant effect, but also to its adverse effects profile (e.g., serotonin toxicity). The latter has raised the question whether it is possible to design out the MAO inhibition properties of MB yet retaining its clinically useful attributes. This study explores this idea further by characterizing five newly synthesized low MAO-A active MB analogues and examining their antidepressant-like properties in the acute forced swim test (FST) in rats, with comparison to imipramine and MB. The results show that all five analogues exhibit antidepressant-like properties in the FST without confounding effects on locomotor activity. The magnitude of these effects is comparable to those of imipramine and MB. Moreover, these newly synthesized MB analogues are markedly less potent MAO-A inhibitors (IC50 = 0.518-4.73 μM) than MB (IC50 = 0.07 μM). We postulate that such lower potency MAO-A inhibitors may present with a reduced risk of adverse effects associated with MAO-A inhibition. While low level MAO-A inhibition still may produce an antidepressant effect, we posit that other MB-related mechanisms may underlie their antidepressant effects, thereby representing a novel group of antidepressant compounds.

中文翻译：

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具有边缘单胺氧化酶抑制作用的亚甲基蓝类似物保留抗抑郁剂样活性。

亚甲蓝（MB）具有多种医疗应用。其中，MB在动物中表现出抗抑郁样作用，并已在治疗情绪障碍的临床试验中显示出希望。作为抗抑郁药，MB可以通过多种机制发挥作用，包括调节一氧化氮环状鸟苷单磷酸（NO-cGMP）级联反应，增强线粒体呼吸作用和抗氧化作用。然而，MB还是单胺氧化酶（MAO）A的高效抑制剂，它最有可能有助于其抗抑郁作用，而且还有助于其不良反应（例如5-羟色胺毒性）。后者提出了一个问题，即是否有可能设计出MB的MAO抑制特性，同时又保留其临床上有用的属性。这项研究通过表征五种新合成的低MAO-A活性MB类似物，并与丙咪嗪和MB进行了比较，在大鼠的急性强迫游泳试验（FST）中检查了它们的抗抑郁样特性，从而进一步探索了这一想法。结果表明，所有五个类似物在FST中均表现出抗抑郁样性质，而对运动活性没有混杂作用。这些影响的程度可与丙咪嗪和MB媲美。此外，这些新合成的MB类似物的有效MAO-A抑制剂（IC50 = 0.518-4.73μM）明显少于MB（IC50 = 0.07μM）。我们推测，这种较低效力的MAO-A抑制剂可以降低与MAO-A抑制有关的不良反应的风险。虽然低水平的MAO-A抑制作用仍可能产生抗抑郁作用，