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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >A potent photoreactive general anesthetic with novel binding site selectivity for GABA(A) receptors
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A potent photoreactive general anesthetic with novel binding site selectivity for GABA(A) receptors

机译：具有新的GABA（A）受体的新型结合位点选择性的有效的光反应性的通用麻醉剂

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摘要

The pentameric gamma-aminobutyric acid type A receptors (GABA(A)Rs) are the major inhibitory ligand-gated ion channels in the central nervous system. They mediate diverse physiological functions, mutations in them are associated with mental disorders and they are the target of many drugs such as general anesthetics, anxiolytics and anti-convulsants. The five subunits of synaptic GABA(A)Rs are arranged around a central pore in the order beta-alpha-beta-alpha-gamma. In the outer third of the transmembrane domain (TMD) drugs may bind to five homologous intersubunit binding sites. Etomidate binds between the pair of beta - alpha subunit interfaces (designated as (beta(+)/alpha(-)) and R-mTFD-MPAB binds to an alpha(+)/beta(-) and an gamma(+)/beta(-) subunit interface (a beta(-) selective ligand). Ligands that bind selectively to other homologous sites have not been characterized. We have synthesized a novel photolabel, (2,6-diisopropyl 4-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)methanol or pTED-di-iPr-BnOH). It is a potent general anesthetic that positively modulates agonist and benzodiazepine binding. It enhances GABA-induced currents, shifting the GABA concentration-response curve to lower concentrations. Photolabeling-protection studies show that it has negligible affinity for the etomidate sites and high affinity for only one of the two R-mTFD-MPAB sites. Exploratory site-directed mutagenesis studies confirm the latter conclusions and hint that pTFDdi-iPr-BnOH may bind between the alpha(+)/beta(-) and alpha(+)/gamma(-) subunits in the TMD, making it an alpha(+) ligand. The latter alpha(+)/gamma(-) site has not previously been implicated in ligand binding. Thus, pTFD-di-iPr-BnOH is a promising new photolabel that may open up a new pharmacology for synaptic GABA A Rs. (C) 2020 Elsevier Masson SAS. All rights reserved.
机译：五聚体γ-氨基丁酸型受体（GABA（A）RS）是中枢神经系统中的主要抑制韧带凝聚的离子通道。它们调节不同的生理功能，它们中的突变与精神障碍有关，它们是许多药物的目标，如全面麻醉剂，抗焦虑和抗痉挛。突触GABA（a）rs的五个亚基布置在β-α-beta-γ-γ中的中央孔周围。在跨膜结构域（TMD）的外部三分之一中，药物可以结合五种同源梭菌结合位点。依赖噻咪酸酯在一对β-α亚基界面之间结合（指定为（β（+）/α（ - ））和R-MTFD-MPAb与α（+）/β（ - ）和γ（+）/ β（ - ）亚单位界面（一个β（ - ）选择性配体）。配体，其结合有选择地其它的同源位点还没有被表征我们已经合成了一种新型photolabel，（2,6-二异丙基-4-（3-（三氟甲基） -3H-二嗪基-3-基）苯基）甲醇或PTED-DI-IPR-BNOH）。它是一种有效的全身麻醉剂，可积极调节激动剂和苯二氮卓的结合。它增强了GABA诱导的电流，将GABA浓度 - 响应曲线转化为较低浓度。 Photolabeling-Prevelation研究表明，对于替代位点，对两个R-MTFD-MPAB位点中的一种具有忽略的亲和力和高亲和力。探索性部位定向诱变研究证实了后一种结论和暗示PTFDDI-IPR-BNOH可以在TMD中的α（+）/β（ - ）和α（+）/γ（ - ）亚基之间结合，使其成为α （+）配体。后者α（+）/γ（ - ）位点以前没有涉及配体结合。因此，PTFD-DI-IPR-BNOH是一个有希望的新光致标签，其可以为突触GABA A RS开辟新的药理学。 （c）2020 Elsevier Masson SAS。版权所有。

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