APPLICATIONS OF MASS SPECTROMETRY IN PHARMACOLOGY

这项计划的重点是化学的发展 葡萄糖醛酸苷。目标包括开发合成的方法 所有类型的葡萄糖醛酸苷，评价和开发新的分析方法 各种葡萄糖醛酸苷的技术，以及对 这些潜在药物代谢物的化学反应性 生理学或分析学意义。我们打算扩大我们的研究范围 酰基连接的葡萄糖醛酸苷的亲电反应性，以及 评价碳醇胺连接的葡萄糖醛酸类化合物的表观反应性。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。我们会 证实并推广了以下假设：酰基连接的葡萄糖醛酸苷在 体内含有谷胱甘肽和蛋白质中的巯基。我们会 继续探索和关联质谱学行为和 不同种类的葡萄糖醛酸苷的特征碎片，依赖于 最主要的是电子碰撞，其次是快原子轰击 和热喷雾电离。我们计划扩大我们的多功能 酶介导的合成法提高了十倍。我们将评估 人肝固定化葡萄糖醛酸基转移酶在生物工程中的应用 药物代谢物的合成。我们建议合成二葡糖醛酸苷， 季铵盐键、碳键键、硫键键和胺键键 葡萄糖醛酸苷的色谱学和质谱学研究 特征，并用作鉴定的参比化合物 体内形成的代谢物。酰基连接和甲醛醇胺连接 将合成用于烷基化研究的葡萄糖醛酸类化合物。

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.