Department of Pharmacology, Faculty of Medicine and Health Sciences, Universite de Sherbrooke, Sherbrooke, QC, Canada.
J Med Chem. 2010 Mar 11;53(5):2063-75. doi: 10.1021/jm9015747.
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and major targets for drug development. Herein, we sought to identify the regions of the human angiotensin II (AngII) type 1 (hAT(1)) receptor binding cleft that interact with all positions of the AngII using photoaffinity labeling. We conducted a complete iterative walk-through of the AngII sequence with either p-benzoyl-L-phenylalanine (Bpa) or p-[3-(trifluoromethyl)-3H-diazirin-3-yl]-L-phenylalanine (Tdf) to yield two series of eight photoreactive analogues. Pharmacological properties assessment of these sixteen analogues showed that the CAM receptor has a structure-activity relationship (SAR) more amenable to the amino acid substitutions at positions 1, 2, 3, and 5 of AngII than the WT receptor. Photoaffinity labeling of the CAM receptor with the selected analogues, which exhibit different but complementary photochemical properties, suggested that the AngII amino-terminus resides in a hydrophilic environment and interacts simultaneously with different regions of the hAT(1) receptor, including several ectodomains.
G 蛋白偶联受体（GPCRs）是细胞表面受体中最大的家族，也是药物开发的主要靶点。在此，我们试图使用光亲和标记法鉴定与人血管紧张素 II（AngII）类型 1（hAT（1））受体结合裂隙相互作用的 AngII 所有位置的区域。我们使用 p-苯甲酰基-L-苯丙氨酸（Bpa）或 p-[3-（三氟甲基）-3H-重氮丙啶-3-基]-L-苯丙氨酸（Tdf）对 AngII 序列进行了完整的迭代遍历，得到了两系列八个光活性类似物。这十六个类似物的药理学特性评估表明，CAM 受体的结构-活性关系（SAR）比 WT 受体更适合 AngII 位置 1、2、3 和 5 的氨基酸取代。用所选类似物对 CAM 受体进行光亲和标记，这些类似物表现出不同但互补的光化学特性，表明 AngII 的氨基末端位于亲水环境中，并与 hAT（1）受体的不同区域同时相互作用，包括几个细胞外结构域。
