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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Novel mouse GABA uptake inhibitors with enhanced inhibitory activity toward mGAT3/4 and their effect on pain threshold in mice
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Novel mouse GABA uptake inhibitors with enhanced inhibitory activity toward mGAT3/4 and their effect on pain threshold in mice

机译：新型小鼠GABA摄取抑制剂，具有增强的MgAT3 / 4的抑制活性及其对小鼠疼痛阈值的影响

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摘要

gamma-Aminobutyric acid (GABA) uptake transporters are membrane transport proteins that are involved in the pathophysiology of a number of neurological disorders. Some types of chronic pain appear to result from the dysfunction of the GABAergic system. The deficiency of mouse GAT1 transporter (mGAT1) abolishes the nociceptive response, which means that mGAT1 inhibition is an appropriate medical approach to achieve analgesia. The mGAT4 transporter is the second most abundant GAT subtype in the brain; however, its physiological role has not yet been fully understood in the central nervous system. In this study, we examined whether the combination of mGAT1 and mGAT3/mGAT4 inhibition in a single molecule might lead to potentially synergistic effects improving analgesic activity to relieve neuropathic pain. To study this hypothesis, new GABA uptake inhibitors were designed, synthesized, and evaluated in terms of their activity and subtype selectivity for mGAT1-4. Among new functionalized amino acid derivatives of serine and GABA analogs, compounds with preferential mGAT3/4 inhibitory activity were discovered. Two selected hits (19b and 31c) were subjected to in vivo tests. We found a statistically significant antiallodynic activity in the von Frey test in diabetic and oxaliplatin-induced neuropathic pain model. The novel compounds (4-hydroxybutanoic, 4-hydroxypentanoic, and 4-aminobutanoic acid derivatives and serine analogs) provide new insights into the structure-activity relationship of mGAT3/mGAT4 inhibitors and indicate a new direction in the search for potential treatment of neuropathic pain of various origin. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：γ-氨基丁酸（GABA）摄取转运蛋白是参与许多神经系统病理学病理学的膜转运蛋白。某些类型的慢性疼痛似乎是由加巴能系统的功能障碍导致的。小鼠GAT1转运蛋白（MGAT1）的缺乏消除了伤害性反应，这意味着MGAT1抑制是实现镇痛的适当医学方法。 MGAT4转运蛋白是大脑中的第二个最丰富的GAT亚型;然而，在中枢神经系统中尚未完全理解其生理作用。在这项研究中，我们检查了单一分子中MgAT1和MgAT3 / MgAT4抑制的组合是否可能导致可能改善镇痛活性的潜在协同作用，以缓解神经性疼痛。为了研究该假设，在其活性和亚型选择性的MgAT1-4方面设计，合成和评估了新的GABA吸收抑制剂。在丝氨酸和GABA类似物的新官能化氨基酸衍生物中，发现了具有优先MgAT3 / 4抑制活性的化合物。对体内测试进行两次选定的命中（19b和31c）。我们在糖尿病和奥沙利铂诱导的神经病疼痛模型中发现了von Frey试验中的统计上显着的抗衰弱性活动。新型化合物（4-羟基甲基，4-羟基丙烯酸和4-氨基丁酸衍生物和丝氨酸类似物）为MGAT3 / MGAT4抑制剂的结构 - 活性关系提供了新的见解，并在寻找神经病疼痛的潜在治疗方面的新​​方向各种起源。 （c）2019年Elsevier Masson SAS。版权所有。

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