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: 3875621
• 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/3875621
• 关键词: adrenergic receptor; alpha adrenergic agent; alpha antiadrenergic agent; beta adrenergic agent; beta antiadrenergic agent; chemical structure function; chemical synthesis; conformation; drug design /synthesis /production; drug metabolism; epinephrine; ethanolamines; fluorine; hormone regulation /control mechanism; neurophysiology; neurotransmitter metabolism; neurotransmitters; norepinephrine; radioassay; radiopharmacology; radiotracer

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 biological tracers. For example, [18 F]-labeled 6-fluorodopamine, the biological precursor to 6-fluoronorepinephrine, has been found to be an excellent scanning agent for peripheral noradrenergic innervation.

生物胺在神经传递、新陈代谢和 各种生理过程的控制。采用多种合成 方法论，包括我们开发的新颖程序，我们已经准备好了 一系列被氟取代的生物胺 环位置。凭借其非常小的尺寸和高 由于电负性，氟是氢的非常有利的替代品 这些类似物。这些物质的生物学特性和用途 环氟化生物胺已被证明是非常有价值的 继续在众多研究中寻找应用，包括研究 运输、储存、释放、代谢的机制和模式 这些胺的作用。特别重要的是发现 6-氟去甲肾上腺素是一种选择性α-肾上腺素能激动剂 2-氟去甲肾上腺素是一种选择性β-肾上腺素能激动剂。机制 解释这些结果的考虑因素包括：1) C-F 的直接影响 激动剂-受体相互作用的键或 2) C-F 的间接影响 键合在乙醇胺侧链的构象上。结果 对合成的新类似物进行测试以探测这些机制表明 电子效应可能比构象因素更重要。 氟化类似物是有用的生物示踪剂。例如，[18 F]-标记的 6-氟多巴胺，生物前体 6-氟去甲肾上腺素，已被发现是一种优秀的扫描剂 用于外周去甲肾上腺素能神经支配。