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。使用各种不同的 合成方法，包括我们开发的新程序，我们 制备了一系列具有氟取代的生物胺 不同的环形位置。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 在这些类似物中。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β-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。因为我们以前合成的FNE产生了外消旋 材料方面，我们对纯R-对映体的合成路线进行了研究。我们 研究了不对称氨羟化反应，对映体选择性 Darzens反应和手性Lewis酸催化羟醛 反应。虽然已经获得了非外消旋产物，但另外 需要研究来实现可接受的产量。为了拥有 2-FNE和6-FNE的可用替代生物前体 苏氨酸和6-氟二羟基苯丝氨酸的合成 (氟-DOPS)外消旋形式，但发现这些类似物很差 芳香氨基酸脱羧酶的底物。这可能是由于 2R-异构体对2S-异构体脱羧基的抑制作用 类似于手性FNE合成的策略，我们是 研究(2S，3R)-氟代DOPS的合成路线。氟化 芳基乙烯胺的制备和作为抑制剂的检测 多巴胺β-羟基酶。

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 is a selective beta-adrenergic agonist and 2- fluoronorepinephrine is a selective beta-adrenergic agonist. Because our previous syntheses of FNE's produced racemic material, we have investigated routes to the pure R-enantiomers. We have examined asymmetric aminohydroxylation reactions, enantioselective Darzens reactions, and the use of chiral Lewis acids to catalyze aldol reactions. Although non-racemic products have been obtained, additional research is need to realize acceptable yields. In order to have available alternate biological precursors for 2-FNE and 6-FNE, we previously synthesized threo-2- and 6-fluorodihydroxy-phenylserine (fluoro-DOPS) in the racemic form, but found these analogues to be poor substrates for aromatic amino acid decarboxylase. This may be due to inhibition of decarboxylation of the 2S-isomer by the 2R-isomer Using similar strategies as applied to the synthesis of chiral FNE's, we are examining routes to homochiral (2S,3R)-fluoro-DOPS. Fluorinated arylacetylenic amines were prepared and examined as inhibitors of dopamine beta-hydroxylase.