INTERACTIONS OF SOME ANALOGS OF THE ANTICONVULSANT MILACEMIDE WITH MONOAMINE-OXIDASE

A series of analogues of the anticonvulsant drug milacemide (2-(n-pent ylamino)-acetamide; Compound I) has been synthesizes: 2-(benzylamino)a cetamide (Compound II), 2-(phenethylamino)acetamide (Compound III), 2- (2-indol-3-yl)-ethylamino acetamide (Compound IV), 2-(2-(5-methoxyindo l-3-yl)ethylamino)-acetamide (Compound V), 2-(2(4-chlorobenzamido)-eth ylamino)acetamide (Compound VI), 2-(2-benzamidoethylamino)-acetamide ( Compound VII) and 2-(4-(3-chlorobenzyloxy)phenthylamino)acetamide (Com pound VIII). These compounds involve retention of the aminoacetamide p ortion of milacemide but replacement of the pentyl moiety with aromati c residues present in the structures of substrates and inhibitors of t he monoamine oxidases. All the compounds tested were substrates for ox liver monoamine oxidase-B (MAO-B), producing an aldehyde that could a ct as a substrate for ox liver aldehyde dehydrogenase and H2O2 as a re sult of oxidative cleavage which also released glycinamide, although t heir Michaelis-Menten parameters differed markedly. None showed detect able activity as substrates for rat liver monoamine oxidase-A (MAO-A). Inhibition of the MAO-B by all the compounds except Compounds VIII an d IV showed marked time dependence and was at least partly irreversibl e. There was no apparent change in the inhibition of MAO-A during enzy me-inhibitor preincubation at 37 degrees for 60 min. Compound VIII was a potent reversible inhibitor of both MAO-A and MAO-B (K-i = 2.8 +/- 0.1 and 4.1 +/- 0.8 mu M), respectively. Comparison of the inhibitory potencies and the specificity constants of the series of compounds as substrates for MAO-B revealed no simple correlations with thier antico nvulsant activities, as measured by their ability to prevent bicuculli ne-induced convlusions and death in the mouse. These results suggest t hat neither inhibition of MAO nor oxidative cleavage by this enzyme to yield glycinamide plays the major role in the anticonvulsant action o f these compounds.