In vivo characterization of T-794, a novel reversible inhibitor of monoamine oxidase-A, as an antidepressant with a wide safety margin.
T-794 is a new reversible inhibitor of MAO type A. In order to predict its clinical utility as an antidepressant, we examined its pharmacological profile (i.e., MAO inhibitory activity, antidepressant-like activity and safety) in vivo in rodents. The p.o. administration of T-794 potentiated L-5-hydroxytryptophan-induced symptoms with ED50 = 1.01 mg/kg (mice) or 1.15 mg/kg (rats), and L-dopa-induced behavior with ED50 = 5.90 mg/kg (mice), whereas it did not alter the effect of beta-phenylethylamine even at 100 mg/kg (mice). In the L-5-hydroxytryptophan test in rats, the activity of T-794 (at twice the dose of ED50) disappeared by 8 h; the duration of action was similar to that of moclobemide. These results confirm the previous biochemical results that MAO-A inhibition by T-794 is highly selective and of short duration. T-794 was effective in three animal models of depression: reserpine reversal (mice, rats), behavioral despair test (mice) and learned helplessness (rats). In these tests, it had potency similar to or greater than moclobemide, tranylcypromine or imipramine. The p.o. administration of T-794 (30 mg/kg) did not affect the pressor effect of tyramine in anesthetized rats, whereas moclobemide (30 mg/kg) and tranylcypromine (6 mg/kg) potentiated the effect. Acute toxicity of T-794 proved to be very low (maximal tolerated dose > 2 g/kg p.o.) in contrast to brofaromine (maximal tolerated dose = 150 mg/kg p.o.). Unlike tricyclic antidepressants, T-794 did not prevent the oxotremorine-induced tremor even at 100 mg/kg p.o.; in this it demonstrated a lack of the anticholinergic activity. These results suggest that T-794 is an effective and particularly safe antidepressant and that it may make an important contribution in the treatment of depressive disorders.
Kato
M
M
Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Japan.
Katayama
T
T
Iwata
H
H
Yamamura
M
M
Matsuoka
Y
Y
Narita
H
H
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology* / Q000633:toxicity; D010080:Oxazoles / Q000494:pharmacology* / Q000633:toxicity; D023303:Oxazolidinones; D051381:Rats; D017208:Rats, Wistar; D014439:Tyramine / Q000494:pharmacology
D000928:Antidepressive Agents; D008996:Monoamine Oxidase Inhibitors; D009281:Naphthalenes; D010080:Oxazoles; D023303:Oxazolidinones; C106442:T 794; D007980:Levodopa; D014439:Tyramine