The recent therapeutic approach in which drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of the multimodal drugs, ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] and the newly designed multifunctional antioxidant iron chelator, M-30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline). Ladostigil combines, in a single molecule, the neuro-protective/neurorestorative effects of the novel anti-Parkinsonian drug and selective monoamine oxidase (MAO)-B inhibitor, rasagiline (Azilect, Teva Pharmaceutical Co.) with the cholinesterase (ChE) inhibitory activity of rivastigmine. A second derivative of rasagiline, M-30 was developed by amalgamating the propargyl moiety of rasagiline into the skeleton of our novel brain permeable neuroprotective iron chelator, VK-28. Preclinical experiments showed that both compounds have anti-Alzheimer’s disease activities and thus, the clinical development is oriented toward treatment of this type of dementia. This review discusses the multimodal effects of two rasagiline-containing hybrid molecules, namely ladostigil and M-30, concerning their neuroprotective molecular mechanisms in vivo and in vitro, including regulation of amyloid precursor protein processing, activation of protein kinase C, and mitogen-activated protein kinase signaling pathways, inhibition of cell death markers and upregulation of neurotrophic factors. Altogether, these scientific findings make these multifunctional compounds potentially valuable drugs for the treatment of Alzheimer’s disease.

中文翻译：

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雷沙吉兰的多功能神经保护衍生物作为抗阿尔茨海默病药物。

最近的治疗方法是将候选药物设计为具有多种药理特性并作用于多个靶标，这刺激了多模式药物 ladostigil (TV3326) [(N-propargyl-(3R)aminoindan-5yl)-ethylmethylcarbamate 的开发。 ] 和新设计的多功能抗氧化铁螯合剂 M-30（5-[N-甲基-N-炔丙基氨基甲基]-8-羟基喹啉）。Ladostigil 在单个分子中结合了新型抗帕金森病药物和选择性单胺氧化酶 (MAO)-B 抑制剂雷沙吉兰（Azilect，梯瓦制药公司）的神经保护/神经修复作用与胆碱酯酶 (ChE) 抑制活性利凡斯的明。雷沙吉兰的二阶衍生物，M-30 是通过将雷沙吉兰的炔丙基部分合并到我们的新型脑渗透性神经保护铁螯合剂 VK-28 的骨架中而开发的。临床前实验表明，这两种化合物都具有抗阿尔茨海默病活性，因此，临床开发的方向是治疗这种类型的痴呆症。这篇综述讨论了两种含有雷沙吉兰的杂化分子，即拉多斯蒂吉尔和 M-30，关于它们的神经保护分子机制的多模式效应在体内和体外，包括淀粉样前体蛋白加工的调节、蛋白激酶 C 的激活和丝裂原激活的蛋白激酶信号通路、细胞死亡标志物的抑制和神经营养因子的上调。总之，这些科学发现使这些多功能化合物成为治疗阿尔茨海默病的潜在有价值的药物。