Effect of milacemide (M) on the levels of dopamine, serotonin and their metabolites in rat substantia nigra and striatum

A series of analogues of the anticonvulsant drug milacemide (2-(n-pentylamino)-acetamide; Compound I) has been synthesized: 2-(benzylamino)acetamide (Compound II), 2-(phenethylamino)acetamide (Compound III), 2-(2-indol-3-yl)-ethylamino acetamide (Compound IV), 2-(2-(5-methoxyindol-3-yl)ethylamino)-acetamide (Compound V), 2-(2(4-chlorobenzamido)-ethylamino)acetamide (Compound VI), 2-(2-benzamidoethylamino)-acetamide (Compound VII) and 2-(4-(3-chlorobenzyloxy)phenethylamino)acetamide (Compound VIII). These compounds involve retention of the aminoacetamide portion of milacemide but replacement of the pentyl moiety with aromatic residues present in the structures of substrates and inhibitors of the monoamine oxidases. All the compounds tested were substrates for ox liver monoamine oxidase-B (MAO-B), producing an aldehyde that could act as a substrate for ox liver aldehyde dehydrogenase and H2O2 as a result of oxidative cleavage which also released glycinamide, although their Michaelis-Menten parameters differed markedly. None showed detectable activity as substrates for rat liver monoamine oxidase-A (MAO-A). Inhibition of the MAO-B by all the compounds except Compounds VIII and IV showed marked time dependence and was at least partly irreversible. There was no apparent change in the inhibition of MAO-A during enzyme-inhibitor preincubation at 37° for 60 min. Compound VIII was a potent reversible inhibitor of both MAO-A and MAO-B (Ki = 2.8 ± 0.1 and 4.1 ± 0.8 μM), 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 their anticonvulsant activities, as measured by their ability to prevent bicuculline-induced convulsions and death in the mouse. These results suggest that neither inhibition of MAO nor oxidative cleavage by this enzyme to yield glycinamide plays the major role in the anticonvulsant action of these compounds.