Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Saints-Pères, 75270 Paris 06, France.
Institut National de la Santé et de la Recherche Médicale (INSERM), U952, Université Pierre et Marie Curie, 9 quai Saint Bernard, 75005 Paris, France; Centre National de la Recherche Scientifique (CNRS) UMR 7224, 9 quai Saint Bernard, 75005 Paris, France; Université Pierre et Marie Curie (UPMC) Paris 06, Pathophysiology of Central Nervous System Disorders, 9 quai Saint Bernard, 75005 Paris, France.
Eur J Med Chem. 2014 May 6;78:236-47. doi: 10.1016/j.ejmech.2014.03.056. Epub 2014 Mar 18.
Vesicular Glutamate Transporters (VGLUTs) allow the loading of presynapic glutamate vesicles and thus play a critical role in glutamatergic synaptic transmission. VGLUTs have proved to be involved in several major neuropathologies and directly correlated to clinical dementia in Alzheimer and Parkinson's disease. Accordingly VGLUT represent a key biological target or biomarker for neuropathology treatment or diagnostic. Yet, despite the pivotal role of VGLUTs, their pharmacology appears quite limited. Known competitive inhibitors are restricted to some dyes as Trypan Blue (TB) and glutamate mimics. This lack of pharmacological tools has heavily hampered VGLUT investigations. Here we report a rapid access to small molecules that combine benefits of TB and dicarboxylic quinolines (DCQs). Their ability to block vesicular glutamate uptake was evaluated. Several compounds displayed low micromolar inhibitory potency when size related compounds are thirty to forty times less potent (i.e. DCQ). We then confirmed the VGLUT selectivity by measuring the effect of the series on vesicular monoamine transport and on metabotropic glutamate receptor activity. These inhibitors are synthesized in only two steps and count among the best pharmacological tools for VGLUTs studies.
囊泡谷氨酸转运体（VGLUTs）允许突触前谷氨酸囊泡的加载，因此在谷氨酸能突触传递中起着关键作用。VGLUT 已被证明参与了几种主要的神经病理学，并与阿尔茨海默病和帕金森病中的临床痴呆直接相关。因此，VGLUT 代表了神经病理学治疗或诊断的关键生物靶标或生物标志物。然而，尽管 VGLUTs 具有关键作用，但它们的药理学似乎相当有限。已知的竞争性抑制剂仅限于一些染料，如锥虫蓝（TB）和谷氨酸类似物。缺乏药理学工具严重阻碍了 VGLUT 的研究。在这里，我们报告了一种快速获得结合 TB 和二羧酸喹啉（DCQ）优势的小分子的方法。评估了它们阻断囊泡谷氨酸摄取的能力。当与大小相关的化合物的效力低至三十至四十倍时，几种化合物表现出低微摩尔抑制效力（即 DCQ）。然后，我们通过测量该系列对囊泡单胺转运和代谢型谷氨酸受体活性的影响，证实了 VGLUT 的选择性。这些抑制剂仅通过两步合成，是 VGLUT 研究的最佳药理学工具之一。
