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: 3964196
• 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/3964196
• 关键词: adrenergic agents; alpha adrenergic agent; analytical method; antihypertensive agents; beta adrenergic agent; chemical binding; chemical structure function; chemical synthesis; dopamine; drug design /synthesis /production; drug screening /evaluation; epinephrine; fluorine; intermolecular interaction; isoproterenol; neurotransmitter metabolism; neurotransmitters; norepinephrine; nuclear magnetic resonance spectroscopy; pharmacology; phenylephrine; positron emission tomography; radioassay; radiopharmacology; radiotracer; serotonin; tyramine

Biogenic amines play key roles in neurotransmission, metabolism, and in control of various physiological processes. Ring-fluorinated analogs have proved to be powerful tools for the study of the mechanisms of transport, storage, release, metabolism and modes of action of these amines since they simulate the geometries of the natural compounds so well. By virtue of its very small size and high electronegativity, fluorine should be a very favorable replacement for hydrogen in these analogs. Some years ago, we developed novel methods for the introduction of fluorine into organic molecules and have applied these methods to the syntheses of a wide variety of biogenic amines with fluorine at various ring positions. The biological properties and usefulness of these ring-fluorinated biogenic amines has proved to be extremely rewarding and continue to find application in a multitude of studies. Perhaps the most significant finding, to date, is that 6-fluoronorepinephrine is a pure alpha-adrenergic agonist, while the 2-fluoro epinephrine is a pure beta-adrenergic agonist. Various explanations for the role of fluorine in creating such specificity have been considered and discarded. We now propose that a critical dipole-dipole repulsion between the benzyllic hydroxyl group and fluorine in the 2- or 6-position confers side chain conformational preference favorable for interaction with the beta- and alpha-adrenergic receptor, respectively. The discovery of increased potency in a fluorinated alpha-adrenergic agonist has both practical and theoretical importance. Chemo-enzymatic methods have been used to prepare radiolabeled fluorinated analogs as well as new analogs as potential prodrugs for melanoma chemotherapy.

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。 环氟化类似物具有 被证明是研究运输机制的有力工具， 这些胺的储存、释放、代谢和作用方式，因为它们 很好地模拟了天然化合物的几何结构。 凭借其 非常小的尺寸和高的电负性，氟应该是一个非常好的选择。 这些类似物中氢的有利替代物。 几年前，我们 开发了将氟引入有机物的新方法， 分子，并已将这些方法应用于各种各样的合成 在不同的环位置上具有氟的生物胺。 生物 这些环氟化生物胺的性质和用途 被证明是非常有益的，并继续在一个 众多的研究。 也许迄今为止最重要的发现是 6-fluoronorepinephrine是一种纯粹的α-肾上腺素能激动剂，而 2-氟肾上腺素是一种纯β-肾上腺素能激动剂。 各种 对氟在产生这种特异性中的作用的解释有 被考虑和抛弃。 我们现在建议， 苄基羟基和氟之间的偶极-偶极排斥 在2-或6-位赋予侧链构象偏好 有利于与β-和α-肾上腺素能受体相互作用， 分别 发现氟化的 α-肾上腺素能激动剂具有实际和理论上的重要性。 化学-酶促方法已用于制备放射性标记的氟化 类似物以及作为黑色素瘤的潜在前药的新类似物 化疗