HALOGENATED BIOGENIC AMINES IN BIOCHEMISTRY AND PHARMACOLOGY

生物胺在神经传递、代谢和代谢中起关键作用， 控制着各种生理过程 使用各种 合成方法，包括我们开发的新程序， 合成了一系列氟取代的生物胺 在不同的环位置。 由于其体积小， 电负性，氟是一个非常有利的替代品， 这些类似物中的氢。 生物学特性和用途 这些环氟化生物胺已被证明是非常 奖励并继续在众多研究中找到应用， 包括对运输，储存，释放， 代谢和这些胺的作用模式。 特别 重要的是发现6-氟诺啡肽（6-FNE）是 选择性α-肾上腺素能激动剂和2-氟肾上腺素（2- FNE）是一种选择性β-肾上腺素能激动剂。 审议的机制 解释这些结果包括：1）C-F键对 激动剂-受体相互作用或2）C-F键的间接作用 乙醇胺侧链的构象。 具有可用 2-FNE和6-FNE的替代生物合成前体，我们有 发展了立体选择性合成苏型-2-和6- 氟二羟基苯基丝氨酸（苏式-FDOPS）。 初始生物学试验 表明这些类似物可能是脱羧酶的不良底物 内切酶 我们已经准备好了全系列的氟化和 多氟多巴胺、去甲肾上腺素和多巴， 相应的藜芦醛，最近由我们使用 芳族底物的亲电性吸附。 审查 多巴胺的单、二和三氟类似物的相互作用 D-1、D-2、D-3和D-4多巴胺受体，以及α 1和α 2 肾上腺素能受体的研究。 的氟化类似物 不可逆的多巴胺β-羟化酶（DBH）抑制剂已经 作为发展DBH靶向的第一步， 用于中枢肾上腺素能受体PET显像的不可逆配体 神经支配 氨基环丙烷羧酸（ACCA）已被 其他人显示，提供保护，免受损害，由于中风， 中枢神经元单氟-和偕-二氟氨基环丙烷 已经制备了羧酸。 初始生物学评价 表明单氟类似物与ACCA等效。 氟化的ACA也是α-氟亚甲基氨基酸， 已知是PLP依赖性的有效抑制剂的衍生物 内切酶

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 analogues. 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 (6-FNE) is a selective alpha-adrenergic agonist and 2-fluoronorepinephrine (2- FNE) 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. To have available alternative biosynthetic precursors of 2-FNE and 6-FNE, we have developed stereoselective syntheses of threo-2- and 6- fluorodihydroxyphenylserine (threo-FDOPS). Initial biological testing suggests that these analogues may be poor substrates for decarboxylase enzymes. We have prepared the complete series of fluorinated and polyfluorinated dopamines, norepinephrines, and DOPAs from the corresponding veratraldehydes, recently prepared by us using electrophilic fluorination of aromatic substrates. Examination of the interactions of the mono-, di-, and trifluoroanalogues of dopamine with D-1, D-2, D-3 and D-4 dopamine receptors, and alpha-1 and alpha-2 adrenergic receptors has been carried out. Fluorinated analogues of irreversible dopamine beta-hydroxlyase (DBH) inhibitors have been prepared as a first step toward the development of DBH-targeted irreversible ligands for PET imaging of central adrenergic innervation. Aminocyclopropane carboxylic acid (ACCA) has been shown by others to provide protection from damage due to stroke to central neurons. Monofluoro- and gem-Difluoroaminocyclopropane carboxylic acids have been prepared. Initial biological evaluation indicates that the monofluoro analogue is equipotent with ACCA. Fluorinated ACCAs are also alpha-flouromethylene amino acids, a class of derivative known to be effective inhibitors of PLP-dependent enzymes.