BEFLOXATONE, A NEW REVERSIBLE AND SELECTIVE MONOAMINE OXIDASE-A INHIBITOR .1. BIOCHEMICAL PROFILE

Befloxatone, a novel oxazolidinone derivative, inhibited selectively a nd competitively monoamine oxidase (MAO)-A in human and rat brain, hea rt, liver and duodenum homogenates with K-i values ranging from 1.9 to 3.6 nM for MAO-A and from 270 to 900 nM for MAO-B. In vitro, befloxat one was more potent at inhibiting MAO-A activity than reference compou nds (befloxatone > harmaline > brofaromine > BW 1370U87 > RS 8359 > to loxatone > moclobemide). The inhibition of MAO-A by befloxatone was ti me-dependent and fully reversible after dilution. After p.o. administr ation, befloxatone induced a dose-dependent and selective inhibition o f rat brain and duodenum MAO-A activities ex vivo with ED(50) values o f 0.06 and 0.025 mg/kg, respectively. Befloxatone (0.5 mg/kg p.o.) dec reased MAO-B activity by only 20% in both tissues. In the brain, liver and duodenum, the inhibition of MAO-A activity by befloxatone was sho rt-lasting. Twenty-four hours after administration of befloxatone (0.7 5 mg/kg p.o.), a full recovery of MAO-A activity was observed in the b rain, 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-hydrox ytryptamine and decreased levels of their respective deaminated metabo lites. These variations were dose-dependent and reversed 24 hr after a dministration. In addition, befloxatone (0.75 mg/kg p.o.) decreased fr ee 3,4-dihydroxyphenylethylene glycol levels in the brain and plasma. Befloxatone (10 mu M) did not modify the activities of diamine or benz ylamine oxidase and did not interact with monoamine uptake mechanisms or with a variety of neurotransmitter or drug receptor sites. In concl usion, the neurochemical profile of befloxatone demonstrates that this compound is a selective, competitive, potent and reversible MAO-A inh ibitor.