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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Development of tricyclic N-benzyl-4-hydroxybutanamide derivatives as inhibitors of GABA transporters mGAT1-4 with anticonvulsant, antinociceptive, and antidepressant activity
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Development of tricyclic N-benzyl-4-hydroxybutanamide derivatives as inhibitors of GABA transporters mGAT1-4 with anticonvulsant, antinociceptive, and antidepressant activity

机译：三环正苄基-4-羟基丁胺衍生物作为GABA转运蛋白MGAT1-4的抑制剂与抗惊厥药，抗伤性和抗抑郁活性

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摘要

gamma-Aminobutyric acid (GABA) neurotransmission has a significant impact on the proper functioning of the central nervous system. Numerous studies have indicated that inhibitors of the GABA transporters mGAT1-4 offer a promising strategy for the treatment of several neurological disorders, including epilepsy, neuropathic pain, and depression. Following our previous results, herein, we report the synthesis, biological evaluation, and structure-activity relationship studies supported by molecular docking and molecular dynamics of a new series of N-benzyl-4-hydroxybutanamide derivatives regarding their inhibitory potency toward mGAT1-4. This study allowed us to identify compound 23a (N-benzyl-4-hydroxybutanamide bearing a dibenzocycloheptatriene moiety), a nonselective GAT inhibitor with a slight preference toward mGAT4 (pIC(50) = 5.02 +/- 0.11), and compound 24e (4-hydroxy-N-[(4-methylphenyl)-methyl]butanamide bearing a dibenzocycloheptadiene moiety) with relatively high inhibitory activity toward mGAT2 (pIC(50) = 5.34 +/- 0.09). In a set of in vivo experiments, compound 24e successively showed predominant anticonvulsant activity and antinociception in the formalin model of tonic pain. In contrast, compound 23a showed significant antidepressant-like properties in mice. These results were consistent with the available literature data, which indicates that, apart from seizure control, GABAergic neurotransmission is also involved in the pathophysiology of several psychiatric diseases, however alternative mechanisms underlying this action cannot be excluded. Finally, it is worth noting that the selected compounds showed unimpaired locomotor skills that have been indicated to give reliable results in behavioral assays. (C) 2021 Elsevier Masson SAS. All rights reserved.
机译：γ-氨基丁酸（GABA）神经传递对中枢神经系统的正常功能有重要影响。大量研究表明，GABA转运体mGAT1-4抑制剂为治疗包括癫痫、神经病理性疼痛和抑郁症在内的几种神经系统疾病提供了一种有希望的策略。根据我们之前的研究结果，我们在此报告了一系列新的N-苄基-4-羟基丁胺衍生物的合成、生物学评价和构效关系研究，这些衍生物的分子对接和分子动力学支持了它们对mGAT1-4的抑制效力。这项研究使我们能够确定化合物23a（含二苯并环庚烯部分的N-苄基-4-羟基丁胺），一种非选择性GAT抑制剂，略微偏向mGAT4（pIC（50）=5.02+/-0.11），以及化合物24e（4-羟基-N-[（4-甲基苯基）-甲基]丁胺，含有二苯并环庚二烯部分），对mGAT2具有相对较高的抑制活性（pIC（50）=5.34+/-0.09）。在一组体内实验中，化合物24e在福尔马林强直性疼痛模型中连续显示出显著的抗惊厥活性和抗伤害作用。相比之下，化合物23a在小鼠体内表现出显著的抗抑郁作用。这些结果与现有文献数据一致，这表明，除了癫痫发作控制外，GABA能神经传递也参与了几种精神疾病的病理生理学，但不能排除这种作用的其他机制。最后，值得注意的是，所选化合物显示出未受影响的运动技能，这些技能已被证明在行为测试中给出了可靠的结果。（c）2021爱思唯尔马松SAS。版权所有。

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