O'Brien E M, Dostert P, Pevarello P, Tipton K F
Department of Biochemistry, Trinity College, Dublin, Ireland.
Biochem Pharmacol. 1994 Aug 30;48(5):905-14. doi: 10.1016/0006-2952(94)90361-1.
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 degrees 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 microM), 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.
已合成了一系列抗惊厥药物米拉酰胺（2 -（正戊基氨基）乙酰胺；化合物I）的类似物：2 -（苄基氨基）乙酰胺（化合物II）、2 -（苯乙氨基）乙酰胺（化合物III）、2 -（2 -（吲哚-3 -基）乙基氨基）乙酰胺（化合物IV）、2 -（2 -（5 -甲氧基吲哚-3 -基）乙基氨基）乙酰胺（化合物V）、2 -（2 -（4 -氯苯甲酰胺基）乙基氨基）乙酰胺（化合物VI）、2 -（2 -苯甲酰胺基乙基氨基）乙酰胺（化合物VII）和2 -（4 -（3 -氯苄氧基）苯乙氨基）乙酰胺（化合物VIII）。这些化合物保留了米拉酰胺的氨基乙酰胺部分，但用单胺氧化酶的底物和抑制剂结构中存在的芳香族残基取代了戊基部分。所有测试的化合物都是牛肝单胺氧化酶-B（MAO - B）的底物，通过氧化裂解产生一种醛，该醛可作为牛肝醛脱氢酶的底物，并产生过氧化氢，同时还释放出甘氨酰胺，尽管它们的米氏参数有显著差异。没有一种化合物作为大鼠肝单胺氧化酶-A（MAO - A）的底物表现出可检测到的活性。除化合物VIII和IV外，所有化合物对MAO - B的抑制都表现出明显的时间依赖性，并且至少部分是不可逆的。在37℃下将酶与抑制剂预孵育60分钟期间，MAO - A的抑制没有明显变化。化合物VIII分别是MAO - A和MAO - B的有效可逆抑制剂（Ki = 2.8±0.1和4.1±0.8 microM）。将该系列化合物作为MAO - B底物的抑制效力和特异性常数与其抗惊厥活性进行比较，结果表明，以其预防荷包牡丹碱诱导的小鼠惊厥和死亡的能力来衡量，它们之间没有简单的相关性。这些结果表明，MAO的抑制作用以及该酶氧化裂解产生甘氨酰胺在这些化合物的抗惊厥作用中均不发挥主要作用。
