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新型 3,4-二氢香豆素的设计与合成:一种具有潜在选择性的单胺氧化酶-B 抑制剂,对帕金森病具有神经保护作用。

Design and synthesis of novel 3,4-dihydrocoumarins as potent and selective monoamine oxidase-B inhibitors with the neuroprotection against Parkinson's disease.

机构信息

School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

出版信息

Bioorg Chem. 2021 Apr;109:104685. doi: 10.1016/j.bioorg.2021.104685. Epub 2021 Feb 2.

Abstract

The monoamine oxidase-B (MAO-B) inhibitors with neuroprotective effects are better for Parkinson's disease (PD) treatment, due to the complicated pathogenesis of PD. To develop new hMAO-B inhibitors with neuroprotection, a novel series of 3,4-dihydrocoumarins was designed as selective and reversible hMAO-B inhibitors to treat PD. Most compounds showed potent and selective inhibition for hMAO-B over hMAO-A with IC values ranging from nanomolar to sub-nanomolar. Among them, compound 4d was the most potent hMAO-B inhibitor (IC = 0.37 nM) being about 20783-fold more active than iproniazid, and exhibited the highest selectivity for hMAO-B (SI > 270,270). Kinetic studies revealed that compound 4d was a reversible and competitive inhibitor of hMAO-B. Neuroprotective studies indicated that compound 4d could protect PC12 cells from the damage induced by 6-OHDA and rotenone. Besides, compound 4d did not exhibit acute toxicity at a dose up to 2500 mg/kg (po), and could cross the BBB in parallel artificial membrane permeability assay. More importantly, compound 4d was able to significantly prevent the motor deficits in the MPTP-induced PD model. These results indicate that compound 4d is an effective and promising candidate against PD.

摘要

单胺氧化酶-B(MAO-B)抑制剂具有神经保护作用,对帕金森病(PD)的治疗更为有效,因为 PD 的发病机制较为复杂。为了开发具有神经保护作用的新型单胺氧化酶-B(MAO-B)抑制剂来治疗 PD,设计了一系列新型 3,4-二氢香豆素作为选择性和可逆性的 hMAO-B 抑制剂。大多数化合物对 hMAO-B 的抑制作用均强于 hMAO-A,IC 值范围为纳摩尔至亚纳摩尔。其中,化合物 4d 是最有效的 hMAO-B 抑制剂(IC = 0.37 nM),对异烟肼的活性约高 20783 倍,对 hMAO-B 的选择性最高(SI > 270,270)。动力学研究表明,化合物 4d 是 hMAO-B 的可逆和竞争性抑制剂。神经保护研究表明,化合物 4d 可保护 PC12 细胞免受 6-OHDA 和鱼藤酮诱导的损伤。此外,化合物 4d 在高达 2500 mg/kg(po)的剂量下不具有急性毒性,并且可以在平行人工膜渗透性测定中穿过血脑屏障。更重要的是,化合物 4d 能够显著预防 MPTP 诱导的 PD 模型中的运动功能障碍。这些结果表明,化合物 4d 是一种有效的、有前景的抗 PD 候选药物。

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