Nishimura K, Lu X, Silverman R B
Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113.
J Med Chem. 1993 Feb 19;36(4):446-8. doi: 10.1021/jm00056a004.
Analogues of the anticonvulsant agent milacemide (1,2-(n-pentylamino)acetamide), in which the carboxamide group is changed to a nitrile (2), a carbethoxy group (3), a carboxylic acid (4), a cyanomethyl group (5), and a trifluoromethyl group (6), were synthesized and tested as substrates and inactivators of monoamine oxidase B (MAO B). The carboxylic acid was neither a substrate nor an inactivator. The trifluoromethyl compound was not soluble in buffer even when organic cosolvents were added, so it could not be tested. All of the other compounds were both substrates and time-dependent irreversible inactivators of MAO B. A plot of the logarithm of kcat/k(inact) (a measure of the efficiency of the inactivators) versus sigma I (Figure 1) shows a linear free energy relationship between the inactivator efficiency and the electron-withdrawing ability of the substituent. As the electron-withdrawing ability increases, the partition ratio decreases indicating that inactivation is becoming more efficient relative to substrate turnover to product. Milacemide was the least efficient of the compounds tested; the nitrile 2 was the most efficient.
合成了抗惊厥剂米拉酰胺（1,2-（正戊基氨基）乙酰胺）的类似物，其中羧酰胺基团被改为腈基（2）、乙氧羰基（3）、羧酸（4）、氰甲基（5）和三氟甲基（6），并将其作为单胺氧化酶B（MAO B）的底物和失活剂进行测试。羧酸既不是底物也不是失活剂。即使添加了有机助溶剂，三氟甲基化合物也不溶于缓冲液，因此无法进行测试。所有其他化合物都是MAO B的底物和时间依赖性不可逆失活剂。kcat/k（inact）的对数（失活剂效率的一种衡量指标）与σI的关系图（图1）显示，失活剂效率与取代基的吸电子能力之间存在线性自由能关系。随着吸电子能力的增加，分配比降低，这表明相对于底物转化为产物，失活变得更有效。米拉酰胺是所测试化合物中效率最低的；腈2是最有效的。
