Schousboe Arne, Wellendorph Petrine, Frølund Bente, Clausen Rasmus P, Krogsgaard-Larsen Povl
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
Adv Neurobiol. 2017;16:283-296. doi: 10.1007/978-3-319-55769-4_14.
Inactivation of GABA-mediated neurotransmission is achieved by high-affinity transporters located at both GABAergic neurons and the surrounding astrocytes. Early studies of the pharmacological properties of neuronal and glial GABA transporters suggested that different types of transporters might be expressed in the two cell types, and such a scenario was confirmed by the cloning of four distinctly different GABA transporters from a number of different species. These GABA-transport entities have been extensively characterized using a large number of GABA analogues of restricted conformation, and several of these compounds have been shown to exhibit pronounced anticonvulsant activity in a variety of animal seizure models. As proof of concept of the validity of this drug development approach, one GABA-transport inhibitor, tiagabine, has been developed as a clinically active antiepileptic drug. This review provides a detailed account of efforts to design new subtype-selective GABA-transport inhibitors aiming at identifying novel antiepileptic drug candidates.
γ-氨基丁酸（GABA）介导的神经传递失活是通过位于GABA能神经元和周围星形胶质细胞的高亲和力转运体实现的。对神经元和胶质细胞GABA转运体药理特性的早期研究表明，两种细胞类型中可能表达不同类型的转运体，从多个不同物种克隆出四种明显不同的GABA转运体证实了这种情况。这些GABA转运实体已使用大量构象受限的GABA类似物进行了广泛表征，其中几种化合物已在多种动物癫痫模型中显示出明显的抗惊厥活性。作为这种药物开发方法有效性的概念验证，一种GABA转运抑制剂噻加宾已被开发成为一种临床活性抗癫痫药物。本综述详细介绍了旨在鉴定新型抗癫痫药物候选物的新型亚型选择性GABA转运抑制剂的设计工作。
