γ-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 (pIC₅₀ = 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 (pIC₅₀ = 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.

γ-氨基丁酸 (GABA) 神经传递对中枢神经系统的正常功能有重大影响。大量研究表明，GABA 转运蛋白 mGAT1-4 的抑制剂为治疗多种神经系统疾病提供了一种有前景的策略，包括癫痫、神经性疼痛和抑郁症。根据我们之前的结果，在此，我们报告了合成、生物学评价和构效关系研究，这些研究得到了一系列新的N-苄基-4-羟基丁酰胺衍生物的分子对接和分子动力学的支持，它们对 mGAT1-4 的抑制效力。这项研究使我们能够鉴定化合物23a ( N-benzyl-4-hydroxybutanamide 带有二苯并环庚三烯部分），一种非选择性 GAT 抑制剂，对 mGAT4 略有偏好（pIC ₅₀  = 5.02 ± 0.11）和化合物24e（4-羟基-N -[（4-甲基苯基）-甲基]带有二苯并环庚二烯部分的丁酰胺）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在强直性疼痛的福尔马林模型中相继显示出主要的抗惊厥活性和镇痛作用。相比之下，化合物23a在小鼠中显示出显着的抗抑郁样特性。这些结果与现有文献数据一致，表明除了控制癫痫发作外，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背后的其他机制。最后，值得注意的是，选定的化合物显示出未受损的运动技能，已表明在行为分析中给出可靠的结果。