Newell J L, Keyari C M, McDaniel S W, Diaz P J, Natale N R, Patel S A, Bridges R J
Center for Structural & Functional Neuroscience, Department of Biomedical & Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Montana, Missoula, MT 59812, United States.
Center for Structural & Functional Neuroscience, Department of Biomedical & Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Montana, Missoula, MT 59812, United States.
Neurochem Int. 2014 Jul;73:132-8. doi: 10.1016/j.neuint.2013.11.012. Epub 2013 Dec 11.
The system xc(-) antiporter is a plasma membrane transporter that mediates the exchange of extracellular l-cystine with intracellular l-glutamate. This exchange is significant within the context of the CNS because the import of l-cystine is required for the synthesis of the antioxidant glutathione, while the efflux of l-glutamate has the potential to contribute to either excitatory signaling or excitotoxic pathology. Changes in the activity of the transport system have been linked to the underlying pathological mechanisms of a variety of CNS disorders, one of the most prominent of which is its highly enriched expression in glial brain tumors. In an effort to produce more potent system xc(-) blockers, we have been using amino-3-carboxy-5-methylisoxazole propionic acid (ACPA) as a scaffold for inhibitor development. We previously demonstrated that the addition of lipophilic aryl groups to either the #4 or #5 position on the isoxazole ring markedly increased the inhibitory activity at system xc(-). In the present work a novel series of analogues has been prepared in which aryl groups have been introduced at both the #4 and #5 positions. In contrast to the competitive action of the mono-substituted analogues, kinetic analyses indicate that the di-substituted isoxazoles block system xc(-)-mediated uptake of (3)H-l-glutamate into SNB-19 cells by a noncompetitive mechanism. These new analogues appear to be the first noncompetitive inhibitors identified for this transport system, as well as being among the most potent blockers identified to date. These diaryl-isoxazoles should be of value in assessing the physiological roles and molecular pharmacology of system xc(-).
系统xc(-)反向转运体是一种质膜转运蛋白，介导细胞外L-胱氨酸与细胞内L-谷氨酸的交换。这种交换在中枢神经系统中具有重要意义，因为L-胱氨酸的摄入是抗氧化剂谷胱甘肽合成所必需的，而L-谷氨酸的流出可能有助于兴奋性信号传导或兴奋性毒性病理过程。转运系统活性的变化与多种中枢神经系统疾病的潜在病理机制有关，其中最突出的之一是其在胶质脑瘤中高度富集表达。为了开发更有效的系统xc(-)阻滞剂，我们一直使用氨基-3-羧基-5-甲基异恶唑丙酸（ACPA）作为抑制剂开发的骨架。我们之前证明，在异恶唑环的4位或5位添加亲脂性芳基可显著提高对系统xc(-)的抑制活性。在本研究中，我们制备了一系列新的类似物，其中在4位和5位都引入了芳基。与单取代类似物的竞争性作用不同，动力学分析表明，二取代异恶唑通过非竞争性机制阻断系统xc(-)介导的(3)H-L-谷氨酸摄取到SNB-19细胞中。这些新的类似物似乎是该转运系统鉴定出的首批非竞争性抑制剂，也是迄今为止鉴定出的最有效的阻滞剂之一。这些二芳基异恶唑在评估系统xc(-)的生理作用和分子药理学方面应具有价值。
