Department of Psychiatry, General University Hospital in Prague, First Faculty of Medicine, Charles University, Ke Karlovu 11, 120 00, Prague 2, Czech Republic.
Institute of Pharmacology, General University Hospital in Prague, First Faculty of Medicine, Charles University, Albertov 4, 128 00, Prague 2, Czech Republic.
Mol Neurobiol. 2021 Mar;58(3):1102-1113. doi: 10.1007/s12035-020-02172-1. Epub 2020 Oct 22.
The trends of novel AD therapeutics are focused on multitarget-directed ligands (MTDLs), which combine cholinesterase inhibition with additional biological properties such as antioxidant properties to positively affect neuronal energy metabolism as well as mitochondrial function. We examined the in vitro effects of 10 novel MTDLs on the activities of mitochondrial enzymes (electron transport chain complexes and citrate synthase), mitochondrial respiration, and monoamine oxidase isoform (MAO-A and MAO-B) activity. The drug-induced effects of 7-MEOTA-adamantylamine heterodimers (K1011, K1013, K1018, K1020, and K1022) and tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers (K1046, K1053, K1056, K1060, and K1065) were measured in pig brain mitochondria. Most of the substances inhibited complex I- and complex II-linked respiration at high concentrations; K1046, K1053, K1056, and K1060 resulted in the least inhibition of mitochondrial respiration. Citrate synthase activity was not significantly inhibited by the tested substances; the least inhibition of complex I was observed for compounds K1060 and K1053, while both complex II/III and complex IV activity were markedly inhibited by K1011 and K1018. MAO-A was fully inhibited by K1018 and K1065, and MAO-B was fully inhibited by K1053 and K1065; the other tested drugs were partial inhibitors of both MAO-A and MAO-B. The tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers K1046, K1053, and K1060 seem to be the most suitable molecules for subsequent in vivo studies. These compounds had balanced inhibitory effects on mitochondrial respiration, with low complex I and complex II/III inhibition and full or partial inhibition of MAO-B activity.
新型 AD 治疗药物的趋势集中在多靶点定向配体（MTDL）上，这些配体结合了胆碱酯酶抑制作用和其他生物学特性，如抗氧化特性，以积极影响神经元能量代谢和线粒体功能。我们研究了 10 种新型 MTDL 对线粒体酶（电子传递链复合物和柠檬酸合酶）、线粒体呼吸和单胺氧化酶同工酶（MAO-A 和 MAO-B）活性的体外影响。在猪脑线粒体中测量了 7-MEOTA-金刚烷胺杂二聚体（K1011、K1013、K1018、K1020 和 K1022）和他克林/7-MEOTA/6-氯他克林-trolox 杂二聚体（K1046、K1053、K1056、K1060 和 K1065）的药物诱导效应。大多数物质在高浓度下抑制复合物 I 和复合物 II 连接的呼吸；K1046、K1053、K1056 和 K1060 导致线粒体呼吸的抑制最小。测试物质对柠檬酸合酶活性没有明显抑制；化合物 K1060 和 K1053 对复合物 I 的抑制最小，而复合物 II/III 和复合物 IV 活性均被 K1011 和 K1018 明显抑制。K1018 和 K1065 完全抑制 MAO-A，K1053 和 K1065 完全抑制 MAO-B；其他测试药物是 MAO-A 和 MAO-B 的部分抑制剂。他克林/7-MEOTA/6-氯他克林-trolox 杂二聚体 K1046、K1053 和 K1060 似乎是最适合进一步体内研究的分子。这些化合物对线粒体呼吸具有平衡的抑制作用，对复合物 I 和复合物 II/III 的抑制作用较低，对 MAO-B 活性具有完全或部分抑制作用。
