A study of the biological pharmacology of IFO, a new selective and reversible monoamine oxidase-B inhibitor.
3-[4-[3-(1H-Imidazol-1-yl)propoxy]phenyl]-5-trifluoromethyl-1,2,4- oxadiazole (IFO), designed to be a novel selective inhibitor of monoamine oxidase (MAO), showed highly selective inhibition for type-B (MAO-B); its IC50 was approximately > 200 microM and 30 nM for type-A (MAO-A) and MAO-B, respectively, in the standard assay using mitochondrial preparations from rat brain or liver. The in vitro MAO-B inhibition by IFO was time-independent, non-competitive and tight-binding; and furthermore, in the presence of sodium cholate its inhibition was not tight-binding and was reversible. Oral administration of IFO (0.5-100 mg/kg) produced a dose-dependent MAO-B inhibition in mouse brain; its ED50 (p.o., 1 hr) was 1.6 mg/kg, while L-deprenyl inhibited the enzyme with the ED50 of approximately 8.0 mg/kg. The ED50 for MAO-A was > 100 mg/kg for either IFO and L-deprenyl. The MAO inhibitive effect of IFO in mouse liver was the same as that in the brain, but that of L-deprenyl in mouse liver was different from that in the brain as shown by the ED50 values of 35 mg/kg and 0.6 mg/kg for MAO-A and MAO-B, respectively. In mice, IFO increased the striatal concentrations of 2-phenylethylamine (2-PEA) and showed almost the same protective efficacy as L-deprenyl against the lethality and striatal dopamine (DA) depletion induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These results indicate that IFO appears to be a potent inhibitor of MAO-B in mouse brain.
Matsumoto
J
J
Research Laboratories, Wakamoto Pharmaceutical Co., Ltd., Kanagawa, Japan.
Takahashi
T
T
Agata
M
M
Toyofuku
H
H
Sasada
N
N
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D004298:Dopamine / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009422:Nervous System Diseases / Q000139:chemically induced / Q000517:prevention & control; D010069:Oxadiazoles / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012642:Selegiline / Q000494:pharmacology
C089469:3-(4-(3-(1H-imidazol-1-yl)propoxy)phenyl)-5-trifluoromethyl-1,2,4-oxadiazole; D015306:Biogenic Monoamines; D008996:Monoamine Oxidase Inhibitors; D010069:Oxadiazoles; D012642:Selegiline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D004298:Dopamine