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.

Abstract

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 (IC50, 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.

• Authors: Shunit Gal, Hailin Zheng, Mati Fridkin, Moussa B H Youdim
• Journal: Journal of neurochemistry (J Neurochem) Vol. 95 Issue 1 Pg. 79-88 (Oct 2005) ISSN: 0022-3042 [Print] England
• PMID: 16181414 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline
• Amines
• Hydroxyquinolines
• Iron Chelating Agents
• Monoamine Oxidase Inhibitors
• Neuroprotective Agents
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Dopamine

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (antagonists & inhibitors, pharmacology)
• Amines (metabolism)
• Animals
• Brain (drug effects, enzymology, metabolism)
• Corpus Striatum (metabolism)
• Dopamine (deficiency)
• Drug Administration Schedule
• Hydroxyquinolines (administration & dosage, pharmacology)
• Hypothalamus (metabolism)
• Iron Chelating Agents (therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Monoamine Oxidase Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Neurodegenerative Diseases (drug therapy)
• Neuroprotective Agents (therapeutic use)
• Parkinson Disease, Secondary (chemically induced, metabolism)