Department of Biomedical and Pharmaceutical Sciences, Center for Structural and Functional Neuroscience, College of Health Professions and Biomedical Sciences, University of Montana, Missoula, MT, 59812, USA.
Department of Chemistry, Carroll College, 1601 N Benton Ave., Helena, MT, 59625, USA.
Neurochem Res. 2021 Mar;46(3):494-503. doi: 10.1007/s11064-020-03182-0. Epub 2021 Jan 4.
The vesicular glutamate transporter (VGLUT) facilitates the uptake of glutamate (Glu) into neuronal vesicles. VGLUT has not yet been fully characterized pharmacologically but a body of work established that certain azo-dyes bearing two Glu isosteres via a linker were potent inhibitors. However, the distance between the isostere groups that convey potent inhibition has not been delineated. This report describes the synthesis and pharmacologic assessment of Congo Red analogs that contain one or two glutamate isostere or mimic groups; the latter varied in the interatomic distance and spacer properties to probe strategic binding interactions within VGLUT. The more potent inhibitors had two glutamate isosteres symmetrically linked to a central aromatic group and showed IC values ~ 0.3-2.0 μM at VGLUT. These compounds contained phenyl, diphenyl ether (PhOPh) or 1,2-diphenylethane as the linker connecting 4-aminonaphthalene sulfonic acid groups. A homology model for VGLUT2 using D-galactonate transporter (DgoT) to dock and identify R88, H199 and F219 as key protein interactions with Trypan Blue, Congo Red and selected potent analogs prepared and tested in this report.
囊泡谷氨酸转运体（VGLUT）促进谷氨酸（Glu）进入神经元囊泡。VGLUT 在药理学上尚未得到充分表征，但有大量研究表明，某些偶氮染料通过连接子携带两个 Glu 等排体，是有效的抑制剂。然而，传递有效抑制作用的等排体基团之间的距离尚未确定。本报告描述了含有一个或两个谷氨酸等排体或模拟体的刚果红类似物的合成和药理学评估；后者在原子间距离和间隔物性质上有所不同，以探测 VGLUT 内的策略性结合相互作用。更有效的抑制剂具有两个谷氨酸等排体，对称连接到中央芳基基团上，在 VGLUT 中的 IC 值约为 0.3-2.0 μM。这些化合物含有苯、二苯醚（PhOPh）或 1,2-二苯乙烷作为连接 4-氨基萘磺酸基团的连接子。使用 D-半乳糖酸盐转运蛋白（DgoT）对 VGLUT2 进行同源建模，以对接并确定 R88、H199 和 F219 作为与锥虫蓝、刚果红和本报告中制备和测试的选定有效类似物的关键蛋白相互作用。
