METABOLITES FROM TERTIARY AMINES--PHENCYCLIDINE

建议进行研究以评估其生物医学意义 通过细胞色素 P-450 介导的代谢形成的亚胺中间体 叔胺。 苯环己哌啶将用作模型化合物来检查 这些亲电子离子对生物大分子的反应性。 代谢依赖性抑制的生化机制 将研究苯环己哌啶的细胞色素 P-450 酶活性 使用体外肝微粒体制剂并重构、纯化 细胞色素 P-450 系统。 亚胺物种将被合成，它们 将研究对模型化合物的反应性，并研究其结构 形成的加合物将通过质谱方法进行表征。 程度 亚胺中间体的形成是组织特有的 物种将通过使用 14CN 捕获方法来确定。 亚胺中间体的形成及其反应的记录 生物大分子应该提供对分子机制的深入了解 与叔胺的毒性作用有关，其中许多是 有用的治疗剂。

Investigations are proposed to assess the biomedical significance of iminium intermediates formed via cytochrome P-450 mediated metabolism of tertiary amines. Phencyclidine will be used as a model compound to examine the reactivity of these electrophilic ions towards biomacromolecules. Biochemical mechanisms underlying metabolism-dependent inhibition of cytochrome P-450 enzymic activities by phencyclidine will be investigated using hepatic microsomal preparations in vitro and reconstituted, purified cytochrome P-450 systems. Iminium species will be synthesized, their reactivity towards model compounds will be studied, and the structure of adducts formed will be characterized by mass spectral methods. The extent to which the formation of iminium intermediates is specific to tissues and species will be determined by use of 14CN- trappping methods. Documentation of the formation of iminium intermediates and their reactions with biomacromolecules should provide insight into the molecular mechanisms associated with the toxic actions of tertiary amines, many of which are useful therapeutic agents.