Damgaard Maria, Haugaard Anne Stæhr, Kickinger Stefanie, Al-Khawaja Anas, Lie Maria E K, Ecker Gerhard F, Clausen Rasmus Prætorius, Frølund Bente
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria.
Adv Neurobiol. 2017;16:315-332. doi: 10.1007/978-3-319-55769-4_16.
γ-Aminobutyric acid (GABA) neurotransmission is terminated by the GABA transporters (GATs) via uptake of GABA into neurons and surrounding glial cells. Four different transporters have been identified: GAT1, GAT2, GAT3, and the betaine/GABA transporter 1 (BGT1). The GAT1 subtype is the most explored transporter due to its high abundance in the brain and the existence of selective and potent GAT1 inhibitors. Consequently, less is known about the role and therapeutic potential of the non-GAT1 subtypes. Emerging pharmacological evidence suggests that some of these transporters pose interesting targets in several brain disorders. Pharmacological non-GAT1-selective tool compounds are important to further investigate the involvement of GATs in different pathological conditions. Extensive medicinal chemistry efforts have been put into the development of subtype-selective inhibitors, but truly selective and potent inhibitors of non-GAT1 subtypes are still limited. This review covers the advances within the medicinal chemistry area and the structural basis for obtaining non-GAT1-selective inhibitors.
γ-氨基丁酸（GABA）神经传递通过GABA转运体（GATs）将GABA摄取到神经元和周围神经胶质细胞中而终止。已鉴定出四种不同的转运体：GAT1、GAT2、GAT3和甜菜碱/GABA转运体1（BGT1）。由于GAT1亚型在大脑中含量丰富且存在选择性强效GAT1抑制剂，因此是研究最多的转运体。因此，对于非GAT1亚型的作用和治疗潜力了解较少。新出现的药理学证据表明，其中一些转运体在几种脑部疾病中是有趣的靶点。药理学上非GAT1选择性工具化合物对于进一步研究GATs在不同病理状况中的参与情况很重要。广泛的药物化学研究致力于开发亚型选择性抑制剂，但真正选择性和强效的非GAT1亚型抑制剂仍然有限。本综述涵盖了药物化学领域的进展以及获得非GAT1选择性抑制剂的结构基础。
