The pharmacological profile of
befloxatone, a reversible, selective and competitive inhibitor of
monoamine oxidase-A has been investigated in rodents. In mice,
befloxatone was more active at potentiating generalized
tremors induced by L-5-hydroxytryptophan (ED50, 0.21 mg/kg p.o.) than phenylethylamine-induced stereotypies (ED50, 58 mg/kg p.o.), indicating a very high in vivo selectivity for inhibition of the A form of
monoamine oxidase.
Befloxatone showed potent activity in behavioral models in rodents predictive of
antidepressant activity (forced swimming test, learned helplessness and
reserpine reversal) with minimal effective doses of 0.1 to 0.2 mg/kg p.o. In these tests,
befloxatone was much more potent (10- to 500-fold) than reference
antidepressant compounds (reversible and irreversible
monoamine oxidase inhibitors and monoamine reuptake inhibitors). In rats,
befloxatone increased rapid eye movement sleep latency and decreased rapid eye movement sleep duration, without rebound effects. Potential
anxiolytic activity was observed in the elevated-plus maze test in rats (minimal effective dose, 1-2 mg/kg p.o.).
Befloxatone had no effect on motor performance, did not induce
sedative or stimulant activity up to doses of 200 mg/kg p.o. and was devoid of
anticholinergic activity in mice. Interaction studies with p.o. dietary
tyramine (12 mg/kg), carried out in freely moving rats, demonstrated that, in contrast to irreversible
monoamine oxidase inhibitors,
befloxatone did not potentiate the pressor effect of this
amine in the range of doses which showed pharmacological activity in
antidepressant behavioral models. Furthermore, of the compounds tested (
moclobemide,
brofaromine,
nialamide and
phenelzine), comparison of doses active in
antidepressant models and doses potentiating the pressor effects of
tyramine demonstrated that
befloxatone had the best therapeutic index. The results suggest that
befloxatone will show clinical
antidepressant activity at low doses and will be devoid of the side effects associated with irreversible
monoamine oxidase inhibitors.