Reactivity of 6-Halopurine Analogs with Glutathione as a Radiotracer for Assessing Function of Multidrug Resistance-Associated Protein 1
| Autor: | Kiyoshi Fukushi, Toshiaki Irie, Toshimitsu Okamura, Tatsuya Kikuchi |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Male
ATP-binding cassette transporter Mice chemistry.chemical_compound Methylpurine Isomerism stomatognathic system Multidrug Resistance Protein 1 Drug Discovery Animals Humans Radioactive Tracers chemistry.chemical_classification Brain Glutathione In vitro Transmembrane protein Rats Kinetics Enzyme Biochemistry chemistry Purines Drug Design Positron-Emission Tomography Molecular Medicine Multidrug Resistance-Associated Protein 1 Multidrug Resistance-Associated Proteins Hydrophobic and Hydrophilic Interactions Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 52:7284-7288 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm901332c |
| Popis: | 6-Bromo-7-[(11)C]methylpurine is reported to react with glutathione via glutathione S-transferases in the brain and to be converted into a substrate for multidrug resistance-associated protein 1 (MRP1), an efflux pump. The compound with a rapid conversion rate allows quantitative assessment of MRP1 function, but this rate is probably susceptible to interspecies differences. Hence, for application to different species, including humans, it is necessary to adjust the conversion rate by modifying the chemical structure. We therefore designed 6-halo-9-(or 7)-[(14)C]methylpurine (halogen: F, Cl, Br, or I), and evaluated them in vitro with respect to enzymatic reactivity with glutathione using brain homogenates from the mouse, rat, or monkey. There was a marked difference in reactivity between these species. Changes in the position of the methyl group and halogen on N-methyl-6-halopurine provided various compounds possessing wide-ranging reactivity with glutathione. In conclusion, the adjustment of reactivity of 6-bromo-7-[(11)C]methylpurine may allow assessment of MRP1 function in the brain in various species. |
| Databáze: | OpenAIRE |
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