Novel di-aryl-substituted isoxazoles act as noncompetitive inhibitors of the system x(c)(-) cystine/glutamate exchanger

作者：Newell J L; Keyari C M; McDaniel S W; Diaz P J; Natale N R; Patel S A; Bridges R J^*

来源：Neurochemistry International, 2014, 73: 132-138.

DOI：10.1016/j.neuint.2013.11.012

• Excitatory amino acid
• Transporter
• xCT
• Uptake
• Glutathione

The system x(c)(-) 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 x(c)(-) 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 x(c)(-). 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 x(c)(-)-mediated uptake of H-3-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.

• 出版日期2014-7