Mitochondrial enzymes are targets of newly synthesized drugs being tested for the treatment of neurodegenerative disorders, such as Alzheimer's disease (AD). The enzyme 17β-hydroxysteroid dehydrogenase type 10 (HSD10) is a multifunctional mitochondrial protein that is thought to play a role in the pathophysiology of AD and is one of the targets of new potential AD drugs. The in vitro effects of frentizole, riluzole, AG18051, and 42 novel modulators of HSD10 (potential AD drugs) on citrate synthase (CS) activity, monoamine oxidase (MAO) activity, complex I- or complex II-linked mitochondrial respiratory rate, and complex I activity were measured in isolated pig brain mitochondria. Based on their minimal inhibitory effects on the respiratory rate of mitochondria and CS and complex I activity, six novel compounds were selected for further testing. Assuming that inhibition of MAO-B could be a desirable effect of AD drugs, only AG18051 and one new compound met the criteria for MAO-B inhibition with minimal drug-induced effects on mitochondrial respiration. In conclusion, our in vitro screening of mitochondrial effect of novel potential AD drugs has enabled the selection of the most promising molecules for further testing that are relatively safe in terms of drug-induced mitochondrial toxicity.

中文翻译：

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新型 17β-羟基类固醇脱氢酶 10 型抑制剂对线粒体呼吸的影响

线粒体酶是新合成药物的靶标，用于治疗神经退行性疾病，如阿尔茨海默病 (AD)。酶 17β-羟基类固醇脱氢酶 10 (HSD10) 是一种多功能线粒体蛋白，被认为在 AD 的病理生理学中起作用，并且是新的潜在 AD 药物的靶点之一。frentizole、riluzole、AG18051 和 42 种新型 HSD10 调节剂（潜在的 AD 药物）对柠檬酸合酶 (CS) 活性、单胺氧化酶 (MAO) 活性、复合物 I 或复合物 II 相关的线粒体呼吸速率的体外影响，以及在分离的猪脑线粒体中测量复合物 I 活性。基于它们对线粒体呼吸频率和 CS 以及复合物 I 活性的最小抑制作用，选择了六种新化合物进行进一步测试。假设抑制 MAO-B 可能是 AD 药物的理想效果，只有 AG18051 和一种新化合物符合 MAO-B 抑制的标准，对线粒体呼吸的药物诱导影响最小。总之，我们对新型潜在 AD 药物的线粒体效应的体外筛选使得能够选择最有希望的分子进行进一步测试，这些分子在药物诱导的线粒体毒性方面相对安全。