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