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Design and Mechanism of GABA Aminotransferase Inactivators. Treatments for Epilepsies and Addictions
Chemical Reviews ( IF 51.4 ) Pub Date : 2018-03-23 00:00:00 , DOI: 10.1021/acs.chemrev.8b00009 Richard B Silverman 1
Chemical Reviews ( IF 51.4 ) Pub Date : 2018-03-23 00:00:00 , DOI: 10.1021/acs.chemrev.8b00009 Richard B Silverman 1
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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.
中文翻译：
GABA 氨基转移酶灭活剂的设计和机制。癫痫和成瘾的治疗
当抑制性神经递质 γ-氨基丁酸 (GABA) 的大脑浓度低于阈值水平时，过度的神经元兴奋会导致抽搐。这种神经传递失衡可以通过抑制 γ-氨基丁酸氨基转移酶 (GABA-AT) 来纠正，该酶催化 GABA 转化为兴奋性神经递质l-谷氨酸。还发现提高 GABA 水平可以拮抗伏核中多巴胺的快速升高和释放，这是成瘾中奖励反应的原因。因此，设计新的 GABA-AT 抑制剂，增加脑 GABA 水平，是癫痫和成瘾新疗法的重要途径。本综述总结了过去 40 年左右的 GABA-AT 基于机制的灭活剂（非反应性化合物，需要目标酶催化其转化为灭活物质，在其释放之前灭活酶）的发现，重点是它们的灭活的催化机制，根据有机化学机制呈现，具有最少的药理学，除非对癫痫和成瘾的活性很重要。专利、摘要、本综述不包括会议记录。此处描述的失活机制可应用于多种不相关酶的失活。
更新日期：2018-03-23
中文翻译：
GABA 氨基转移酶灭活剂的设计和机制。癫痫和成瘾的治疗
当抑制性神经递质 γ-氨基丁酸 (GABA) 的大脑浓度低于阈值水平时，过度的神经元兴奋会导致抽搐。这种神经传递失衡可以通过抑制 γ-氨基丁酸氨基转移酶 (GABA-AT) 来纠正，该酶催化 GABA 转化为兴奋性神经递质l-谷氨酸。还发现提高 GABA 水平可以拮抗伏核中多巴胺的快速升高和释放，这是成瘾中奖励反应的原因。因此，设计新的 GABA-AT 抑制剂，增加脑 GABA 水平，是癫痫和成瘾新疗法的重要途径。本综述总结了过去 40 年左右的 GABA-AT 基于机制的灭活剂（非反应性化合物，需要目标酶催化其转化为灭活物质，在其释放之前灭活酶）的发现，重点是它们的灭活的催化机制，根据有机化学机制呈现，具有最少的药理学，除非对癫痫和成瘾的活性很重要。专利、摘要、本综述不包括会议记录。此处描述的失活机制可应用于多种不相关酶的失活。
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