A potent photoreactive general anesthetic with novel binding site selectivity for GABAA receptors
作者:Abdelrahman R. Shalabi、Zhiyi Yu、Xiaojuan Zhou、Youssef Jounaidi、Hanwen Chen、Jiajia Dai、Daniel E. Kent、Hua-Jun Feng、Stuart A. Forman、Jonathan B. Cohen、Karol S. Bruzik、Keith W. Miller
DOI:10.1016/j.ejmech.2020.112261
日期:2020.5
transmembrane domain (TMD) drugs may bind to five homologous intersubunit binding sites. Etomidate binds between the pair of β – α subunit interfaces (designated as β+/α–) and R–mTFD-MPAB binds to an α+/β– and an γ+/β– subunit interface (a β– selective ligand). Ligands that bind selectively to other homologous sites have not been characterized. We have synthesized a novel photolabel, (2,6-diisopropyl-4
五聚体A型γ-氨基丁酸受体(GABA A Rs)是中枢神经系统中主要的抑制配体门控离子通道。它们介导多种生理功能,其中的突变与精神障碍有关,并且它们是诸如全身麻醉药,抗焦虑药和抗惊厥药等许多药物的靶标。突触GABA A Rs的五个亚基以β-α-β-α-γ的顺序排列在中心孔周围。在跨膜结构域(TMD)的外部三分之一中,药物可能会结合到五个同源的亚基结合位点。该对β之间依托咪酯结合- α亚基接口(命名为β + /α - )和R-mTFD-MPAB结合到α + /β -和γ+ /β -亚单位界面(一个β -选择性配体)。尚未选择性结合其他同源位点的配体。我们已经合成了一种新型的光敏标签,(2,6-二异丙基-4-(3-(三氟甲基)-3H-二氮杂-3-基)苯基)甲醇或pTFD-di-iPr-BnOH。这是一种有效的全身麻醉剂,可积极调节激动剂和苯并二氮杂卓的结合。它增强了GABA诱导的电流,将GAB