M30, a novel multifunctional neuroprotective drug with potent iron chelating and brain selective monoamine oxidase-ab inhibitory activity for Parkinson's disease.
Iron and monoamine oxidase activity are increased in brain of Parkinson's disease (PD). They are associated with autoxidation and oxidative deamination of dopamine by MAO resulting in the generation of reactive oxygen species and the onset of oxidative stress to induce neurodegeneration. Iron chelators (desferal, Vk-28 and clioquinol) but not copper chelators have been shown to be neuroprotective in the 6-hydroxydoapmine and MPTP models of Parkinson's disease (PD), as are monoamine oxidase B inhibitors such as selegiline and rasagiline. These findings prompted the development of multifunctional anti PD drugs possessing iron chelating phamacophore of VK-28 and the propargylamine MAO inhibitory activity of rasagiline. M30 is a potent iron chelator, radical scavenger and brain selective irreversible MAO-A and B inhibitor, with little inhibition of peripheral MAO. It has neuroprotective activity in in vitro and in vivo models of PD and unlike selective MAO-B inhibitors it increases brain dopamine, serotonin and noradrenaline. These findings indicate beside its anti PD action, it may also possess antidepressant activity, similar to selective MAO-A and nonselective MAO inhibitors. These properties make it an ideal anti PD drug for which it is being developed.
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Eve Topf and US National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases, Technion-Faculty of Medicine, Haifa, Israel.
Fridkin
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Amit
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Zheng
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Youdim
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D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D004298:Dopamine / Q000502:physiology; D015259:Dopamine Agents / Q000633:toxicity; D006801:Humans; D006912:Hydroxyquinolines / Q000627:therapeutic use*; D007502:Iron Chelating Agents / Q000627:therapeutic use*; D008996:Monoamine Oxidase Inhibitors / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy*; D009435:Synaptic Transmission / Q000187:drug effects
C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D015259:Dopamine Agents; D006912:Hydroxyquinolines; D007502:Iron Chelating Agents; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine