Preclinical profile of befloxatone, a new reversible MAO-A inhibitor

Befloxatone, a novel oxazolidinone derivative, is a potent, selective and r eversible monoamine oxidase A (MAO-A) inhibitor in vitro (K-1A = 1.9-3.6 nM ) and ex vivo (ED50 MAO-A = 0.02 mg/kg, p.o.). It does not interact with a large number of receptors, monoamine transporters or other amine oxidases. Binding studies with [H-3]-befloxatone in rat brain sections show that it l abels with high affinity (K-d=1.3 nM) a single population of sites with the pharmacological characteristics and regional distribution of MAO-A. In the rat brain, befloxatone (0.75 mg/kg, i.p.) increases tissue levels of monoa mines and decreases levels of their deaminated metabolites, Acute administr ation of befloxatone (0.75 mg/kg, i.p.) induces an increase in extracellula r striatal dopamine and cortical norepinephrine but not cortical serotonin levels in the rat. Befloxatone (1 mg/kg, i.p.) potently inhibits the firing rate of serotonergic neurons, partially decreases the firing of noradrener gic neurons and has no effect on the firing of dopaminergic neurons (a mirr or image of its effects on monoamine release in terminal regions), suggesti ng that the relative effects of befloxatone on monoamine release may be gov erned by autoreceptor-mediated control of monoaminergic neurons at the cell body level. Befloxatone (0.03-0.3 mg/kg, p.o,) exhibits potent activity in behavioural models predictive of antidepressant activity. Befloxatone (up to 1.5 mg/kg, p.o.) does not potentiate the pressor effects of orally admin istered tyramine at centrally active doses and duodenal [H-3]-befloxatone b inding is displaced by increasing doses of orally administered tyramine (0. 1-40 mg/kg, i.p.). These results suggest that befloxatone is a potent rever sible MAO-A inhibitor with antidepressant potential and a wide safety margi n with regard to the potentiation of the presser effect of tyramine. (C) 19 98 Elsevier Science BSI. All rights reserved.