A Study of the Biological Pharmacology of IFO, a New Selective and Reversible Monoamine Oxidase-B Inhibitor

Abstract

3-[4-[3-(1H-Imidazol-1-yl)propoxy]phenyl]-5-trifluoromethyl-1, 2, 4-oxadiazole (IFO), design ed to be a novel selective inhibitor of monoamine oxidase (MAO), showed highly selective inhibition for type-B (MAO-B); its IC₅₀ was approximately > 200 μM 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.