Design and Mechanism of GABA Aminotransferase Inactivators. Treatments for Epilepsies and Addictions.
Design and Mechanism of GABA Aminotransferase Inactivators. Treatments for Epilepsies and Addictions.
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DOI：
10.1021/acs.chemrev.8b00009
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发表时间：
2018-04-11
期刊：
影响因子：
62.1
通讯作者：
Silverman RB
中科院分区：
文献类型：
--
作者：
Silverman RB
当抑制性神经递质γ-氨基丁酸（GABA）的脑浓度降低到阈值以下时，过度的神经元兴奋可导致抽搐。这种神经传递的不平衡可以通过抑制γ-氨基丁酸转氨酶（GABA- at）来纠正，GABA催化GABA转化为兴奋性神经递质l -谷氨酸。研究还发现，提高GABA水平可以对抗伏隔核中多巴胺的快速升高和释放，而多巴胺是成瘾中的奖励反应。因此，设计新的GABA- at抑制剂，提高大脑GABA水平，是癫痫和成瘾新治疗的重要途径。本文综述了近40年来基于机制的GABA-AT失活剂（非活性化合物，需要靶酶催化其转化为失活物质，在释放前使酶失活）的发现，重点介绍了其失活的催化机制，根据有机化学机制提出，除了对癫痫和成瘾的活性重要外，药理作用最小。本综述不包括专利、摘要和会议记录。这里描述的失活机制可以应用于多种不相关酶的失活。
When the brain concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) diminishes below a threshold level, the excess neuronal excitation can lead to convulsions. This imbalance in neurotransmission can be corrected by inhibition of the enzyme γ-aminobutyric acid aminotransferase (GABA-AT), which catalyzes the conversion of GABA to the excitatory neurotransmitter L-glutamic acid. It also has been found that raising GABA levels can antagonize the rapid elevation and release of dopamine in the nucleus accumbens, which is responsible for the reward response in addiction. Therefore, the design of new inhibitors of GABA-AT, which increases brain GABA levels, is an important approach to new treatments for epilepsy and addiction. This review summarizes findings over the last 40 or so years of mechanism-based inactivators (unreactive compounds that require the target enzyme to catalyze their conversion to the inactivating species, which inactivate the enzyme prior to their release) of GABA-AT with emphasis on their catalytic mechanisms of inactivation, presented according to organic chemical mechanism, with minimal pharmacology, except where important for activity in epilepsy and addiction. Patents, abstracts, and conference proceedings are not covered in this review. The inactivation mechanisms described here can be applied to the inactivations of a wide variety of unrelated enzymes.
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影响因子：
2.1
作者：
BIRD, CW
通讯作者：
BIRD, CW
影响因子：
3.6
作者：
ADAMS, JL;CHEN, TM;METCALF, BW
通讯作者：
METCALF, BW
影响因子：
3.3
作者：
BERNASCONI, R;KLEIN, M;SCHMUTZ, M
通讯作者：
SCHMUTZ, M
影响因子：
3.6
作者：
BEY, P;GERHART, F;JUNG, M
通讯作者：
JUNG, M
DOI：
10.1111/j.1432-1033.1979.tb13195.x
发表时间：
1979-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
BOUCLIER, M;JUNG, MJ;LIPPERT, B
通讯作者：
LIPPERT, B