Nitroindazole compounds inhibit the oxidative activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to neurotoxic pyridinium cations by human monoamine oxidase (MAO).
Monoamine oxidase (MAO) B is a mitochondrial enzyme selectively involved in the oxidative activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to toxic pyridinium cations producing Parkinsonism in animal models. Various synthesized 5-nitroindazoles, 6-nitroindazole and the neuroprotectant 7-nitroindazole were examined as inhibitors of MAO and as antioxidants and radical scavengers. The oxidation of MPTP by human MAO-B and mitochondria was assessed by HPLC. Simple nitroindazoles inhibited MPTP oxidation to 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP(+)) and 1-methyl-4-phenylpyridinium (MPP(+)) in a competitive and reversible manner. 5-Nitroindazole (IC(50)=0.99 microM, K(i)=0.102 microM) and 6-nitroindazole (IC(50)=2.5 microM) were better inhibitors of human MAO-B than 7-nitroindazole (IC(50)=27.8 microM). 6-Nitroindazole also inhibited MAO-A. Nitroindazole isomers were good hydroxyl radical (OH(*)) scavengers, with 5-nitro-, 6-nitro- and 7-nitroindazole showing similar activity (k approximately 10(10) M(-1) s(-1)). Neuroprotective actions of nitroindazoles (7-nitroindazole) could be linked to their MAO-inhibitory and antiradical properties besides inhibition on nitric oxide synthase (NOS). 5-Nitro- and 6-nitroindazole, previously reported as weak NOS inhibitors, were better inhibitors of human MAO-B and more active against MPTP neurotoxin oxidation (lower MPDP(+) and MPP(+) levels) than 7-nitroindazole and acted as good radical scavengers and could be potential neuroprotective agents in addition to MAO-B inhibitors.
Herraiz
Tomas
T
Instituto de Fermentaciones Industriales, Spanish Council for Scientific Research, Madrid, Spain. therraiz@ifi.csic.es
Arán
Vicente J
VJ
Guillén
Hugo
H
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D011726:Pyridinium Compounds / Q000378:metabolism*
D016166:Free Radical Scavengers; D007191:Indazoles; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D011726:Pyridinium Compounds; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase