4-Amino-2-(substituted methyl)-2-butenoic acids: substrates and potent inhibitors of gamma-aminobutyric acid aminotransferase.
4-Amino-2-(substituted methyl)-2-butenoic acids: substrates and potent inhibitors of gamma-aminobutyric acid aminotransferase.
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4-氨基-2-（取代甲基）-2-丁烯酸：γ-氨基丁酸转氨酶的底物和有效抑制剂。
DOI：
10.1021/jm00155a029
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发表时间：
1986
影响因子：
7.3
通讯作者：
Invergo,BJ
中科院分区：
文献类型：
--
作者：
Silverman,RB;Durkee,SC;Invergo,BJ
以CBZ保护的4-氨基丁酸叔丁酯为原料合成了4-氨基-2-(取代甲基)-2-丁烯酸，其中X(取代基)=F、Cl、OH。苯基硒和羟甲基在-碳上的连续取代，然后在羟甲基上消除了氧化硒和卤化物的取代，以良好的产率得到了化合物。在氧化硒消除步骤中观察到了意想不到的立体选择性，该步骤产生了所需的E异构体作为唯一产物。这些化合物补充了两个以前报道的系列化合物(Silverman，R.B.；Levy，.A.生物化学。生物群落。[中英文摘要]Re.Commun.1980，95,250-255；J.Biol。化学。1981、256、11565-11568)，并用于绘制γ-氨基丁酸氨基转移酶(GABAT)活性部位的一段图谱。这些化合物都不是GABA-T的时间依赖性失活剂，但都是强有力的竞争性可逆抑制剂；羟基化合物的K值为5微米。这些化合物不是钝化剂，这表明X的消除不会发生，或者在消除后的适当位置上没有活性部位亲核试剂用于反应。使用氟类似物，证明了酶催化的氟离子释放，表明确实发生了消除。与前两个系列的化合物不同(OP.如图所示)其中当取代基是卤素时发生排他性消除，但羟基取代类似物的排他性转氨基占优势，在这里描述的系列中，氟类似物给出了4：1的消除与转氨基的比率。这表明，2，3-双键稳定了含氟化合物与磷酸吡哆醛之间席夫碱的氮烯丙基异构化产物。本文的结果表明，基于机理的GABA-T灭活剂的设计不应基于酶结合的GABA的2位附近的电泳体产生。此外，用2-羟甲基(或其他氢键取代基)和2，3-双键取代一种抑制剂，可使分子与GABA-T有良好的结合特性。已有研究表明，当大脑中的γ-氨基丁酸(GABA)水平降至临界量以下时，可发生惊厥，脑内直接给药GABA可终止癫痫发作。然而，1‘3然而，GABA不会越过血脑屏障，血脑屏障是阻止外源物质进入大脑的保护膜。因此，GABA不是一种有效的抗惊厥剂。最近，人们一直致力于发现抑制γ-氨基丁酸氨基转移酶(EC2.6)的化合物。1.19；GABA-T)，45678‘9是一种负责GABA分解代谢的脑酶。这将导致成本增加-
4-Amino-2-(substituted methyl)-2-butenoic acids, where X (the substituted group)= F, Cl, OH, are synthesized from Cbz-protected tert-butyl 4-aminobutanoate. Successive substitutions at the-carbon by phenylseleno and hydroxymethyl groups, followed byelimination of the selenoxide and halide substitution at the hydroxymethyl group, afford the compounds in good yields. An unexpected degree of stereoselectivity is observed in the selenoxide elimination step, which yields the desired E isomer as the sole product. These compounds complement two previously reported series of compounds (Silverman, R. B.; Levy,. A. Biochem. Biophys. Res. Commun. 1980, 95, 250-255; J. Biol. Chem. 1981, 256, 11565-11568) and are used in an approach to map a section of theactive site of y-aminobutyric acid aminotransferase (GABA-T). None of these compounds is a time-dependent inactivator of GABA-T, but all are potent competitive reversible inhibitors; the hydroxy compound has a K, value of 5 µ. That these compounds are not inactivators suggests that either elimination of X does not occur or that there is no active site nucleophile in the appropriate position for reaction following elimination. With use of the fluoro analogue, enzyme-catalyzed fluoride ion release is demonstrated, indicating that elimination does occur. Unlike the previous two series of compounds (op. cit.) in which exclusive elimination occurs when the substituent is a halogen but exclusive transamination prevails for the hydroxyl-substituted analogues, in the series described here, the fluoro analoguegives a 4: 1 ratio of elimination to transamination. This suggests that the 2, 3-double bond stabilizes the product of azallylic isomerization of the Schiff base between the fluoro compound and pyridoxal phosphate. The results described here indicate that the design of a mechanism-based inactivator for GABA-T should not be based on electrophile generation near the 2-position of enzyme-bound GABA. Furthermore, substitution of an inhibitor with a 2-hydroxymethyl group (or other hydrogen-bonding substituent) and a 2, 3-double bond may lend auspicious binding propertiesto the molecule for GABA-T.It has been shown that convulsions can occur when the level of y-aminobutyric acid (GABA) in the brain dimin-ishes below a critical amount and that direct administra-tion of GABA into the brain terminates the seizures. 1'3 However, GABA does not cross the blood-brain barrier, a protective membrane that prevents xenobiotics from entering the brain. Consequently, GABA is not an effec-tive anticonvulsant agent. Recently, efforts have been directed toward the discovery of compounds that inhibit y-aminobutyric acid aminotransferase (EC 2.6. 1.19; GABA-T), 4 5678'9 a brain enzyme responsible for the catabolism of GABA. This would result in an increase in the con-