HALOGENATED BIOGENIC AMINES IN BIOCHEMISTRY AND PHARMACOLOGY

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。 使用多种合成 方法，包括我们开发的新程序，我们有 制备了一系列不同氟取代的生物胺， 环的位置。 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 这些机制没有明确区分这两种基本的 机制等 氟化类似物与克隆的野生型和 突变肾上腺素能受体正在被研究， 受体蛋白上的特定位点负责氟诱导 肾上腺素能选择性 氟化类似物是有用的机械 探针和生物示踪剂。 [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。 我们 已经开发了苏型-2-和6-的立体选择性合成， 氟代二羟基苯基丝氨酸（氟代DOPS）。 这些将作为 用于制备2-和6-氟诺啡肽的前药 中枢神经系统 非对映选择性和对映选择性 [18F]-标记-苏-6-氟-DOPS作为PET扫描剂的方法 中枢肾上腺素能神经支配的研究 合成新 氟化和多氟化藜芦醛， 亲电键合，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.