E2011, A NOVEL, SELECTIVE AND REVERSIBLE INHIBITOR OF MONOAMINE-OXIDASE TYPE-A

E2011, )benzothiazol-6-yl]-5-methoxymethyl-2-oxazolidine, is a novel i nhibitor of monoamine oxidase type A (MAO-A). We have characterized th e neurochemical and pharmacological profiles of E2011 and compared the m with those of known inhibitors of MAO-A, E2011 potently inhibited MA O-A with more than 30,000 times higher selectivity for MAO-A relative to MAO-B in rat brain homogenate. E2011 did not affect putative neural receptors or reuptake of biogenic amines into synaptosomes of rat bra in, which suggests that it is specific to monoaminergic systems. In vi vo, E2011 at a dose of 0.3 mg/kg p.o. exhibited potent MAO-A inhibitor y activity, whereas MAO-B inhibition was not observed even at 100 mg/k g p.o. E2011 inhibited monoamine metabolism in the rat brain, but the effect disappeared 24 h after administration. Like other reversible MA O-A inhibitors, E2011 did not show a cumulative inhibitory effect duri ng repeated administration for 7 days. However, inhibition of MAO-A by E2011 in ex vivo experiments appeared to be less potent than that by moclobemide. The MAO-A inhibition by E2011 was partially but significa ntly reversed by dialysis at 4 degrees C for 24 h, which indicates tha t E2011 could be dissociated from the enzyme. These findings suggest t hat E2011 is a reversible and highly selective inhibitor of MAO-A. The potency of inhibition by highly reversible MAO-A inhibitors such as E 2011 is likely to be underestimated in ex vivo studies because of dilu tion of the homogenate in the assay system.