HALOGENATED BIOGENIC AMINES IN BIOCHEMISTRY AND PHARMACOLOGY

生物胺在神经传递、新陈代谢和 对各种生理过程的控制。使用各种合成材料 方法，包括我们开发的新程序，我们有 制备了一系列不同取代氟的生物胺 吊环位置。由于它的体积很小，高度很高 电负性，氟是氢的一种非常有利的替代品 在这些类比中。它们的生物学特性和用途 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 运输、储存、释放、代谢等机制的研究 以及这些胺的作用方式。特别重要的是 发现6-氟肾上腺素是一种选择性的α-肾上腺素能 激动剂和2-氟肾上腺素是一种选择性β-肾上腺素能 激动剂。解释这些结果的机制包括：1)a) C-F键对激动剂-受体相互作用的直接影响 C-F键对乙醇胺构象的间接影响 侧链。新合成的类似物对探针的测试结果 这些机制并没有明确区分这两个基本的 机械装置。含氟类似物与克隆的野生型和 目前正在研究突变的肾上腺素能受体，试图识别 氟诱导的受体蛋白上的特定位点 肾上腺素能选择性。氟化类似物是有用的机械原理 探测器和生物示踪剂。[18F]-标记6-氟多胺， 6-氟肾上腺素的生物前体已被发现是一种 外周去甲肾上腺素能神经支配的极佳扫描剂。我们 发展了苏氨酸-2-和6-苏氨酸的立体选择性合成 氟二羟基苯丝氨酸(F-DOPS)。这些将被研究为 用于精制2-和6-氟肾上腺素的前体药物 中枢神经系统。非对映选择性和对映选择性 [18F]标记苏氨酸-6-氟-DOPS作为PET扫描剂的研究进展 对于中枢肾上腺素能神经支配的研究已经发展起来。一种新的合成 氟化和多氟藜芦醛，基于直接 亲电氟化，已经实现。

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 have not clearly differentiated between these two basic mechanisms. Binding of fluorinated analogs to cloned wild-type and mutant adrenergic receptors is now being studied to try to identify specific sites on the receptor protein responsible for fluorine-induced adrenergic selectivities. Fluorinated analogs are useful mechanistic probes and biological tracers. [18F]-labeled 6-fluorodopamine, the biological precursor to 6-fluoronorepinephrine, has been found to be an excellent scanning agent for peripheral noradrenergic innervation. We have developed stereoselective syntheses of threo-2- and 6- fluorodihydroxyphenylserine (fluoro-DOPS). These will be studied as prodrugs for the elaboration of 2-and 6-fluoronorepinephrine in the central nervous system. Diasteroselective and enantioselective approaches to [18F]-labelled-threo-6-fluoro-DOPS as a PET-scanning agent for central adrenergic innervation have been developed. A new synthesis of fluorinated and polyfluorinated veratraldehydes, based on direct electrophilic fluorination, has been realized.