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.