Selective inhibition of gamma-aminobutyric acid aminotransferase by (3R,4R),(3S,4S)- and (3R,4S),(3S,4R)-4-amino-5-fluoro-3-phenylpentanoic acids.
Selective inhibition of gamma-aminobutyric acid aminotransferase by (3R,4R),(3S,4S)- and (3R,4S),(3S,4R)-4-amino-5-fluoro-3-phenylpentanoic acids.
复制标题
(3R,4R),(3S,4S)- 和 (3R,4S),(3S,4R)-4-氨基-5-氟-3-苯基戊酸选择性抑制 γ-氨基丁酸转氨酶。
DOI：
10.1021/jm00165a008
复制
发表时间：
1990
影响因子：
7.3
通讯作者：
Nanavati,SM
中科院分区：
文献类型：
--
作者：
Silverman,RB;Nanavati,SM
(3fi，4fi），（3S，4S）-和（3fi，4S），（3S，47？）-合成了4-氨基-5-氟-3-苯基戊酸（1a和1b），并研究了其对γ-氨基丁酸（GABA）氨基转移酶的选择性抑制作用。这两种化合物都没有引起酶的时间依赖性失活。无论是化合物under wentenzyme催化的转氨作用，也不是氟离子消除从任何化合物的酶。没有检测到3-苯基乙酰丙酸，即HF消除后烯胺水解的产物。然而，la和lb都是GABA氨基转移酶的竞争性可逆抑制剂，la的Km小于GABA的Km。这些结果表明，la和lb结合到GABA氨基转移酶的活性位点，但7-质子去除不发生。（S）-4-氨基-5-氟戊酸（AFPA）是谷氨酸脱羧酶（GAD）的强抑制剂，但在浓度为AFPA的40倍时，无论是1a还是1b都不能引起可检测到的竞争性抑制。兴奋性和抑制性神经递质L-谷氨酸和-氨基丁酸（GABA）的浓度分别在中枢神经系统（CNS）中主要由两种PLP依赖性酶，L-谷氨酸脱羧酶，催化L-谷氨酸转化为GABA的酶和GABA转氨酶，将GABA降解为琥珀酸半醛的酶。2通过将GABA在中枢神经系统中的浓度降低到一定水平以下5或阻断其作用，GABA无法正常发挥功能3，4，在这些系统中观察到惊厥状态。6 GABA水平增加到阈值以上通常会导致对这些癫痫发作的保护。3，4，7直接给予GABA作为抗惊厥剂的简单性由于其不渗透通过血脑屏障（即膜）的事实而复杂化
(3fi, 4fi),(3S, 4S)-and (3fi, 4S),(3S, 47?)-4-amino-5-fluoro-3-phenylpentanoic acid (la and lb) were synthesized and studied as selective inactivatorsof-aminobutyric acid (GABA) aminotransferase. Neither compound caused time-dependent inactivation of theenzyme. Neither compound underwentenzyme-catalyzed transamination nor was fluoride ion eliminated from either compound by the enzyme. No 3-phenyllevulinic acid, theproduct of elimination of HF followed by enamine hydrolysis, was detected. However, both la and lb were competitive reversible inhibitors of GABA aminotransferase; the K¡ for la was smaller than the Km for GABA. These results suggest that la and lb bind to the active site of GABA aminotransferase, but 7-proton removal does not occur. Whereas (S)-4-amino-5-fluoropentanoic acid (AFPA) is a potent inhibitor of L-glutamic acid decarboxylase (GAD), neither la nor lb at concentrations 40 times the K¡ of AFPA caused any detectable competitive inhibition of GAD. Therefore, the incorporation of a phenyl substituent at the 3-position of AFPA confirms selective inhibition of GABA aminotransferase over GAD.The concentrations of the excitatory and inhibitory neurotransmitters L-glutamate and-aminobutyric acid (GABA), 1 11respectively, are regulated in the central nervous system (CNS) principally by two PLP-dependent enzymes, L-glutamic acid decarboxylase, the enzyme that catalyzes the conversion of L-glutamate to GABA and GABA aminotransferase, the enzyme that degrades GABA to succinic semialdehyde. 2 Convulsive states have been observed in systems where GABA is prevented from functioning nor-mally3, 4 either by the lowering of its concentration in the CNS below a certain level5 or by blocking its effect. 6 An increase in GABA levels above the threshold limit usually results in protection against these seizures. 3, 4, 7 The sim-plicity of administering GABA directly as an anticonvulsant agent is complicated by the fact that it does not permeate through the blood-brain barrier, ie, a membrane