HALOGENATED BIOGENIC AMINES IN BIOCHEMISTRY AND PHARMACOLOGY

生物化学和药理学中的卤化生物胺

• 批准号: 3776295
• 负责人: K L KIRK
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3776295
• 关键词: alpha adrenergic agent; amines; beta adrenergic agent; chemical structure function; conformation; fluoridation; fluorine; halogenation; neuropharmacology; neurotransmitter metabolism; neurotransmitters

Biogenic amines play key roles in neurotransmission, metabolism, and in control of various physiological processes. Using a variety of synthetic methodologies, including novel procedures developed by us, we have prepared a series of biogenic amines with fluorine substituted at various ring-positions. By virtue of its very small size and high electronegativity, fluorine is a very favorable replacement for hydrogen in these analogs. The biological properties and usefulness of these ring-fluorinated biogenic amines have proved to be extremely rewarding and continue to find applications in a multitude of studies, including research on the mechanisms of transport, storage, release, metabolism, and modes of action of these amines. Of particular significance was the discovery that 6-fluoronorepinephrine is a selective alpha-adrenergic agonist and 2-fluoronorepinephrine is a selective beta-adrenergic agonist. Mechanisms considered to explain these results include: 1) a direct effect of the C-F bond on agonist-receptor interaction or 2) an indirect effect of the C-F bond on the conformation of the ethanolamine side-chain. The results of testing of new analogs synthesized to probe these mechanisms indicate that electronic effects may be more important than conformational factors. Fluorinated analogs are useful mechanistic probes and biological tracers. The increased phenol acidities of fluorinated catecholamines proved to be an effective probe for details of the mechanisms of catechol methylation by the enzyme, catechol O- methyltransferase. We now have used the increased phenol acididites of fluorinated norepinephrines to study further the relationship between pH and adrenergic activity. [18F]-labeled 6-fluorodopamine, the biological precursor to 6-fluoronorepinephrine, has been found to be an excellent scanning agent for peripheral noradrenergic innervation. Research is in progress to develop central noradrenergic scanning agents based on this series.

生物胺在神经传递、代谢和代谢中起着关键作用。 控制各种生理过程。 使用各种 合成方法，包括我们开发的新程序，我们 合成了一系列氟取代的生物胺， 不同的环位置。 由于其体积小， 由于电负性，氟是氢的非常有利的替代物 在这些类似物中。 这些生物学特性和有用性 环氟化生物胺已被证明是非常有益的 并继续在众多研究中找到应用，包括 对运输、储存、释放、代谢机制的研究， 以及这些胺的作用方式。 特别重要的是， 发现6-氟肾上腺素是选择性α-肾上腺素能 激动剂和2-氟诺啡肽是一种选择性β-肾上腺素能 激动剂 解释这些结果的机制包括：1） C-F键对激动剂-受体相互作用的直接影响，或2） C-F键对乙醇胺构象的间接影响 侧链 合成的新类似物的检测结果 这些机制表明，电子效应可能更重要 而不是构象因素。 氟化类似物是有用的机械 探针和生物示踪剂。 增加的苯酚酸度 氟化的儿茶酚胺被证明是一种有效的探针， 邻苯二酚O-甲基化酶的作用机制 甲基转移酶。 我们现在已经使用了 氟化去甲肾上腺素，以进一步研究 pH值和肾上腺素活性。 [18F]-标记的6-氟多巴， 已发现6-氟酮肾上腺素的生物前体是一种 外周去甲肾上腺素能神经支配的优良扫描剂。 研究正在进行中，以开发中枢去甲肾上腺素能扫描剂 基于这个系列。