BEFLOXATONE, A NEW REVERSIBLE AND SELECTIVE MONOAMINE OXIDASE-A INHIBITOR .2. PHARMACOLOGICAL PROFILE

The pharmacological profile of befloxatone, a reversible, selective an d competitive inhibitor of monoamine oxidase-A has been investigated i n rodents. In mice, befloxatone was more active at potentiating genera lized tremors induced by L-5-hydroxytryptophan (ED(50), 0.21 mg/kg p.o .) than phenylethylamine-induced stereotypies (ED(50), 58 mg/kg p.o.), indicating a very high in vivo selectivity for inhibition of the A fo rm of monoamine oxidase. Befloxatone showed potent activity in behavio ral models in rodents predictive of antidepressant activity (forced sw imming 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 c ompounds (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 dura tion, without rebound effects. Potential anxiolytic activity was obser ved 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. a nd was devoid of anticholinergic activity in mice. Interaction studies with p.o. dietary tyramine (12 mg/kg), carried out in freely moving r ats, demonstrated that, in contrast to irreversible monoamine oxidase inhibitors, befloxatone did not potentiate the presser effect of this amine in the range of doses which showed pharmacological activity in a ntidepressant behavioral models. Furthermore, of the compounds tested (moclobemide, brofaromine, nialamide and phenelzine), comparison of do ses active in antidepressant models and doses potentiating the presser effects of tyramine demonstrated that befloxatone had the best therap eutic index. The results suggest that befloxatone will show clinical a ntidepressant activity at low doses and will be devoid of the side eff ects associated with irreversible monoamine oxidase inhibitors.