Befloxatone, a new reversible and selective monoamine oxidase-A inhibitor. I. Biochemical profile.

Befloxatone, a novel oxazolidinone derivative, inhibited selectively and competitively monoamine oxidase (MAO)-A in human and rat brain, heart, liver and duodenum homogenates with Ki values ranging from 1.9 to 3.6 nM for MAO-A and from 270 to 900 nM for MAO-B. In vitro, befloxatone was more potent at inhibiting MAO-A activity than reference compounds (befloxatone > harmaline > brofaromine > BW 137OU87 > RS 8359 > toloxatone > moclobemide). The inhibition of MAO-A by befloxatone was time-dependent and fully reversible after dilution. After p.o. administration, befloxatone induced a dose-dependent and selective inhibition of rat brain and duodenum MAO-A activities ex vivo with ED50 values of 0.06 and 0.025 mg/kg, respectively. Befloxatone (0.5 mg/kg p.o.) decreased MAO-B activity by only 20% in both tissues. In the brain, liver and duodenum, the inhibition of MAO-A activity by befloxatone was short lasting. Twenty-four hours after administration of befloxatone (0.75 mg/kg p.o.), a full recovery of MAO-A activity was observed in the brain, but the enzyme activity was still decreased by 38 and 56% in the duodenum and liver, respectively. In the rat brain, befloxatone (0.75 mg/kg p.o.) increased levels of norepinephrine, dopamine and 5-hydroxytryptamine and decreased levels of their respective deaminated metabolites. These variations were dose-dependent and reversed 24 hr after administration. In addition, befloxatone (0.75 mg/kg p.o.) decreased free 3,4-dihydroxyphenylethylene glycol levels in the brain and plasma. Befloxatone (10 microM) did not modify the activities of diamine or benzylamine oxidase and did not interact with monoamine uptake mechanisms or with a variety of neurotransmitter or drug receptor sites. In conclusion, the neurochemical profile of befloxatone demonstrates that this compound is a selective, competitive, potent and reversible MAO-A inhibitor.

Effects of befloxatone, a new potent reversible MAO-A inhibitor, on cortex and striatum monoamines in freely moving rats.

Single administration of befloxatone (0.75 mg/kg, i.p.) in the rat increased extracellular levels of DA (+300%) in striatum. In frontal cortex, befloxatone (0.75 mg/kg, i.p.) and nialamide (100 mg/kg, i.p.) increased NA by +100% but did not modify 5HT, whereas pargyline (100 mg/kg i.p.) increased extracellular NA and 5HT by 400 and 600%, respectively. At these doses, befloxatone inhibited totally and selectively MAO-A, pargyline inhibited totally MAO-A and MAO-B. Increases of tissue and extracellular concentrations of NA and 5HT were highest after Pargyline suggesting that both monoamines may be metabolized by MAO-A and MAO-B. Befloxatone and nialamide potentiated the effects of idazoxan (20 mg/kg, i.p.) on extracellular NA in frontal cortex, which increased from 350% to 2,000 and 1,500% respectively. These results suggest that alpha 2-adrenoceptors play a major role in the regulation of extracellular NA in frontal cortex.