Krall Jacob, Balle Thomas, Krogsgaard-Larsen Niels, Sørensen Troels E, Krogsgaard-Larsen Povl, Kristiansen Uffe, Frølund Bente
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
Adv Pharmacol. 2015;72:201-27. doi: 10.1016/bs.apha.2014.10.003. Epub 2014 Dec 4.
A high degree of structural heterogeneity of the GABAA receptors (GABAARs) has been revealed and is reflected in multiple receptor subtypes. The subunit composition of GABAAR subtypes is believed to determine their localization relative to the synapses and adapt their functional properties to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown for only a few orthosteric ligands. Still, these examples show that it is indeed possible to obtain orthosteric subtype selectivity and they serve as models for further development in the orthosteric GABAAR ligand area. This review presents the very few existing structural classes of orthosteric GABAAR antagonists and describes the development of potent antagonists from partial agonists originally derived from the potent GABAAR agonist muscimol. In this process, several heterocyclic aromatic systems have been used in combination with structural models in order to map the orthosteric binding site and to reveal structural details to be used for obtaining potency and subtype selectivity. The challenges connected to functional characterization of orthosteric GABAAR partial agonists and antagonists, especially with regard to GABAAR stoichiometry and alternative binding sites are discussed. GABAAR antagonists have been essential in defining the tonic current but both remaining issues concerning the GABAARs involved and the therapeutic possibilities of modulating tonic inhibition underline the need for GABAAR antagonists with improved selectivity.
γ-氨基丁酸A型受体（GABAARs）具有高度的结构异质性，这在多种受体亚型中有所体现。GABAAR亚型的亚基组成被认为决定了它们相对于突触的定位，并使其功能特性适应GABA作用的局部时间模式，从而实现相位性或紧张性抑制。特异性GABAAR拮抗剂是从生理和药理学角度阐明不同类型GABAAR抑制作用的重要工具。然而，仅对少数正构配体显示出受体亚型（群体）之间的明显选择性。尽管如此，这些例子表明确实有可能获得正构亚型选择性，并且它们可作为正构GABAAR配体领域进一步发展的模型。本综述介绍了现有的极少数正构GABAAR拮抗剂的结构类别，并描述了从最初源自强效GABAAR激动剂蝇蕈醇的部分激动剂开发强效拮抗剂的过程。在此过程中，几种杂环芳香体系已与结构模型结合使用，以绘制正构结合位点并揭示用于获得效力和亚型选择性的结构细节。讨论了与正构GABAAR部分激动剂和拮抗剂的功能表征相关的挑战，特别是关于GABAAR化学计量和替代结合位点的挑战。GABAAR拮抗剂对于定义紧张性电流至关重要，但与所涉及的GABAAR相关的剩余问题以及调节紧张性抑制的治疗可能性都强调了需要具有更高选择性的GABAAR拮抗剂。
