title: Novel di-aryl-substituted isoxazoles act as noncompetitive inhibitors of the system Xc(-) cystine/glutamate exchanger.
abstract: 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(-).
authors: Center for Structural & Functional Neuroscience, Department of Biomedical & Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Montana, Missoula, MT 59812, United States.
authors: J L
authors: JL
authors: Newell
authors: Center for Structural & Functional Neuroscience, Department of Biomedical & Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Montana, Missoula, MT 59812, United States.
authors: C M
authors: CM
authors: Keyari
authors: Center for Structural & Functional Neuroscience, Department of Biomedical & Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Montana, Missoula, MT 59812, United States.
authors: S W
authors: SW
authors: McDaniel
authors: Center for Structural & Functional Neuroscience, Department of Biomedical & Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Montana, Missoula, MT 59812, United States.
authors: P J
authors: PJ
authors: Diaz
authors: Center for Structural & Functional Neuroscience, Department of Biomedical & Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Montana, Missoula, MT 59812, United States.
authors: N R
authors: NR
authors: Natale
authors: Center for Structural & Functional Neuroscience, Department of Biomedical & Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Montana, Missoula, MT 59812, United States.
authors: S A
authors: SA
authors: Patel
authors: Center for Structural & Functional Neuroscience, Department of Biomedical & Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Montana, Missoula, MT 59812, United States. Electronic address: richard.bridges@umontana.edu.
authors: R J
authors: RJ
authors: Bridges
mesh_terms: D027182:Amino Acid Transport System y+ / Q000037:antagonists & inhibitors*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D005971:Glutamates / Q000737:chemistry / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D013329:Structure-Activity Relationship
chemical_list: D027182:Amino Acid Transport System y+; D005971:Glutamates; D007555:Isoxazoles; C118895:SLC7A11 protein, human; D018698:Glutamic Acid; C041409:4-amino-3-chloro-2-pentenedioic acid
keywords: Excitatory amino acid; Glutathione; Transporter; Uptake; xCT