Design and Mechanism of (S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic Acid, a Highly Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Addiction.
Design and Mechanism of (S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic Acid, a Highly Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Addiction.
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DOI：
10.1021/jacs.7b10965
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发表时间：
2018-02-14
影响因子：
15
通讯作者：
Silverman RB
中科院分区：
文献类型：
--
作者：
Juncosa JI;Takaya K;Le HV;Moschitto MJ;Weerawarna PM;Mascarenhas R;Liu D;Dewey SL;Silverman RB
γ -氨基丁酸（GABA）是中枢神经系统中主要的抑制性神经递质。抑制GABA氨基转移酶（GABA-AT），一种降解GABA的吡哆醛5′-磷酸（PLP）依赖性酶，已被确定为治疗药物滥用的一种可能策略。已经发现，由于这种抑制而发生的GABA水平升高，可以拮抗在成瘾物质的急性刺激后腹侧纹状体（中脑核）中多巴胺的快速释放。此外，已知GABA水平升高也可在癫痫患者中引起抗惊厥作用。我们之前设计了基于机制的灭活剂（1 S，3S）-3-氨基-4-二氟亚甲基-1-环戊酸（2），现在称为CPP-115，其灭活GABA-AT的效率是氨己烯酸的186倍，氨己烯酸是FDA批准的唯一一种GABA-AT灭活剂。CPP-115被发现具有治疗可卡因成瘾和各种癫痫的高治疗潜力，已成功完成I期安全性临床试验，并被发现有效治疗婴儿痉挛症（West综合征）。在此，我们报告了一种新的基于机理的灭活剂（S）-3-氨基-4-（二氟亚甲基）环己-1-烯-1-羧酸（5）的设计、分子动力学模拟、合成和生物学评价，发现其作为GABA-AT的灭活剂的效率比CPP-115高近10倍。我们还提出了意想不到的晶体结构5绑定到GABA-AT，以及用于协助结构阐明过程的计算分析。此外，发现5具有有利的药代动力学性质和低脱靶活性。在自由活动的大鼠中的体内研究表明，在抑制纹状体中多巴胺的释放方面，5显著上级于CPP-115，所述纹状体中多巴胺的释放在急性可卡因或尼古丁攻击之后发生。化合物5还减弱了海马体中增加的代谢需求（神经元葡萄糖代谢），海马体是编码关于动物接受强化或厌恶药物的环境的空间信息的大脑区域。这种多学科的计算设计的临床前疗效的方法应适用于设计和改进的其他酶的晶体结构和失活机制是已知的机制为基础的抑制剂。
γ -Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. Inhibition of GABA aminotransferase (GABA-AT), a pyridoxal 5′-phosphate (PLP)-dependent enzyme that degrades GABA, has been established as a possible strategy for the treatment of substance abuse. The raised GABA levels that occur as a consequence of this inhibition have been found to antagonize the rapid release of dopamine in the ventral striatum (nucleus accumbens) that follows an acute challenge by an addictive substance. In addition, increased GABA levels are also known to elicit an anticonvulsant effect in patients with epilepsy. We previously designed the mechanism-based inactivator (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (2), now called CPP-115, that is 186 times more efficient in inactivating GABA-AT than vigabatrin, the only FDA-approved drug that is an inactivator of GABA-AT. CPP-115 was found to have high therapeutic potential for the treatment of cocaine addiction and for a variety of epilepsies, has successfully completed a Phase I safety clinical trial, and was found to be effective in the treatment of infantile spasms (West syndrome). Herein we report the design, using molecular dynamics simulations, synthesis, and biological evaluation of a new mechanism-based inactivator, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (5), which was found to be almost 10 times more efficient as an inactivator of GABA-AT than CPP-115. We also present the unexpected crystal structure of 5 bound to GABA-AT, as well as computational analyses used to assist the structure elucidation process. Furthermore, 5 was found to have favorable pharmacokinetic properties and low off-target activities. In vivo studies in freely moving rats showed that 5 was dramatically superior to CPP-115 in suppressing the release of dopamine in the corpus striatum, which occurs subsequent to either an acute cocaine or nicotine challenge. Compound 5 also attenuated increased metabolic demands (neuronal glucose metabolism) in the hippocampus, a brain region that encodes spatial information concerning the environment in which an animal receives a reinforcing or aversive drug. This multidisciplinary computational design to preclinical efficacy approach should be applicable to the design and improvement of mechanism-based inhibitors of other enzymes whose crystal structures and inactivation mechanisms are known.
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影响因子：
3.3
作者：
Banik, Sindrila Dutta;Chandra, Amalendu
通讯作者：
Chandra, Amalendu
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
2.9
作者：
GLOSS, LM;KIRSCH, JF
通讯作者：
KIRSCH, JF
影响因子：
4.8
作者：
IVERSEN, LL;BIRD, ED;RAYNER, CN
通讯作者：
RAYNER, CN
影响因子：
15
作者：
Lee, Hyunbeom;Doud, Emma H.;Silverman, Richard B.
通讯作者：
Silverman, Richard B.