APPLICATIONS OF MASS SPECTROMETRY IN PHARMACOLOGY

该计划的重点是化学的发展 葡萄糖醛酸苷。 目标包括开发方法， 葡萄糖醛酸苷类化合物，评价和开发新的 各种葡萄糖醛酸苷的技术， 这些药物代谢物的化学反应性， 生理或分析意义。 我们建议扩大我们的研究 酰基连接的葡糖苷酸的亲电反应性， 评价甲醇胺连接的葡萄糖醛酸苷的表观反应性。 我们 将开发技术来区分形成的位置酯异构体 通过酰基糖苷键的重排自发地产生。 我们将 证实并扩展了酰基连接的葡萄糖醛酸苷在 体内与谷胱甘肽和蛋白质中的巯基。 我们将 继续探索和关联质谱行为， 不同种类的葡萄糖醛酸苷的特征断裂，依赖于 主要是电子碰撞，其次是快速原子轰击 和热喷雾电离。 我们建议扩大我们的多功能 酶介导的合成方法的一个因素的十。 我们将评估 从人肝固定的葡糖醛酸基转移酶用于 药物代谢物的合成。 我们建议合成二葡萄糖醛酸， 季铵连接、碳连接、硫连接和胺连接 葡萄糖醛酸苷类化合物的色谱和质谱研究 特性和用作鉴别的参比化合物 体内形成的代谢物。 酰基连接和甲醇胺连接 将合成葡糖苷酸用于烷基化研究。

The focus of this program is the development of the chemistry of glucuronides. Objectives include the development of methods to synthesize glucuronides of all types, evaluation and development of new analytical techniques for various kinds of glucuronides, and assessment of the chemical reactivities of these drug metabolites which have potential physiologic or analytical significance. We propose to expand our studies of the electrophillic reactivity of acyl-linked glucuronides, and to evaluate the apparent reactivity of carbinolaminelinked glucuronides. We will develop techniques to distinguish positional ester isomers formed spontaneously by rearrangement of the acyl glycosidic linkage. We will confirm and extend the hypothesis that acyl-linked glucuronides react in vivo with glutathione and with sulfhydryl groups in protein. We will continue to explore and correlate the mass spectral behavior and characteristic fragmentation of different kinds of glucuronides, relying most heavily on electron impact and secondarily on fast atom bombardment and thermospray ionization. We propose to scale up our versatile enzyme-mediated synthetic method by a factor of ten. We will evaluate the utility of glucuronyl transferase immobilized from human liver for synthesis of drug metabolites. We propose to synthesize diglucuronides, quaternary ammonium-linked, carbon-linked, sulfur-linked and amine-linked glucuronides in order to study their chromatographic and mass spectral characteristics and for use as reference compounds for identification of metabolites formed in vivo. Acyl-linked and carbinolamine-linked glucuronides will be synthesized for alkylation studies.