Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion
Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion
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DOI：
10.1111/j.1471-4159.2005.03341.x
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发表时间：
2005-10-01
影响因子：
4.7
通讯作者：
Youdim, MBH
中科院分区：
文献类型：
--
作者：
Gal, S;Zheng, H;Youdim, MBH
以具有单胺氧化酶（MAO）和神经保护作用的N-炔丙胺（N-propargylamine）为药效团的铁螯合剂VK-28为原料，合成了几种多功能铁螯合剂。他们有铁螯合效力类似desferal。M30是一种有效的体外不可逆大鼠脑线粒体MAO-A和-B抑制剂（IC（50），MAO-A，0.037 +/-0.02; MAO-B，0.057 +/-0.01）。急性（1 - 5 mg/kg）和慢性（5 - 10 mg/kg）腹膜内（i.p.）或口服（p.o.）每天一次，持续14天]体内研究显示M30是有效的脑选择性（纹状体、海马和小脑）MAO-A和-B抑制剂。对肝脏和小肠的酶活性影响不大。其N-去甲基化衍生物M30A的活性显著降低。在纹状体和下丘脑中测定，M30急性和慢性给药导致多巴胺（DA）、5-羟色胺（5-HT）、去甲肾上腺素（NA）水平升高，DOPAC（二羟基苯乙酸）、HVA（高香草酸）和5-HIAA（5-羟基吲哚乙酸）水平降低。在帕金森病（PD）的小鼠MPTP（N-甲基-4-苯基-1，2，3，6-四氢吡啶）模型中，它减弱神经毒素的DA消耗作用，并增加纹状体DA、5-HT和NA水平，同时减少它们的代谢产物。由于DA被MAO-A和-B同样良好地代谢，因此预期M30在PD中将具有比选择性MAO-B抑制剂更大的DA神经传递增强作用，因为MAO-B抑制剂不改变脑多巴胺。
Several multifunctional iron chelators have been synthesized from hydroxyquinoline pharmacophore of the iron chelator, VK-28, possessing the monoamine oxidase (MAO) and neuroprotective N-propargylamine moiety. They have iron chelating potency similar to desferal. M30 is a potent irreversible rat brain mitochondrial MAO-A and -B inhibitor in vitro (IC(50), MAO-A, 0.037 +/- 0.02; MAO-B, 0.057 +/- 0.01). Acute (1-5 mg/kg) and chronic [5-10 mg/kg intraperitoneally (i.p.) or orally (p.o.) once daily for 14 days]in vivo studies have shown M30 to be a potent brain selective (striatum, hippocampus and cerebellum) MAO-A and -B inhibitor. It has little effects on the enzyme activities of the liver and small intestine. Its N-desmethylated derivative, M30A is significantly less active. Acute and chronic treatment with M30 results in increased levels of dopamine (DA), serotonin(5-HT), noradrenaline (NA) and decreases in DOPAC (dihydroxyphenylacetic acid), HVA (homovanillic acid) and 5-HIAA (5-hydroxyindole acetic acid) as determined in striatum and hypothalamus. In the mouse MPTP (N-methy-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease (PD) it attenuates the DA depleting action of the neurotoxin and increases striatal levels of DA, 5-HT and NA, while decreasing their metabolites. As DA is equally well metabolized by MAO-A and -B, it is expected that M30 would have a greater DA neurotransmission potentiation in PD than selective MAO-B inhibitors, for which it is being developed, as MAO-B inhibitors do not alter brain dopamine.