Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
Eur J Med Chem. 2019 Jul 1;173:203-212. doi: 10.1016/j.ejmech.2019.04.016. Epub 2019 Apr 12.
Due to the complexity of the pathogenesis of Parkinson's disease (PD), multimodal treatment may achieve better results. In this study, a series of coumarin Mannich base derivatives were designed and synthesized as multifunctional agents for PD treatment. Among the derivatives, 3-(3-(dimethylamino)propanoyl)-7-hydroxy-5-methyl- 2H-chromen-2-one hydrochloride (24) exhibited the most potent and selective hMAO-B inhibitory activity, and anti-inflammatory and neuroprotective effects in the in vitro studies. It significantly attenuated PD-associated behavioural deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Furthermore, preliminary mechanistic studies indicated that 24 could selectively inhibit MAO-B activity, decrease the neuroinflammatory process, and protect tyrosine hydroxylase-immunopositive dopaminergic neurons. These results suggest that 24 is a promising multifunctional agent for effective therapy for PD.
由于帕金森病（PD）的发病机制复杂，采用多模态治疗可能会取得更好的效果。在本研究中，设计并合成了一系列香豆素曼尼希碱衍生物，作为治疗 PD 的多功能药物。在这些衍生物中，3-(3-(二甲基氨基)丙酰基)-7-羟基-5-甲基-2H-色烯-2-酮盐酸盐（24）在体外研究中表现出最强和最选择性的 hMAO-B 抑制活性、抗炎和神经保护作用。它能显著减轻 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 小鼠模型中与 PD 相关的行为缺陷。此外，初步的机制研究表明，24 可以选择性地抑制 MAO-B 活性，减少神经炎症过程，并保护酪氨酸羟化酶免疫阳性多巴胺能神经元。这些结果表明，24 是一种很有前途的多功能药物，可有效治疗 PD。
