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: 6161946
• 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/6161946
• 关键词: alpha adrenergic agent; beta adrenergic agent; chemical structure function; chemical substitution; chemical synthesis; conformation; dopamine; epinephrine; fluorine; halogenation; neuropharmacology; neurotransmitter agonist; neurotransmitter antagonist; neurotransmitter metabolism; neurotransmitters; norepinephrine; prodrugs

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.

生物胺在神经传递、新陈代谢和 各种生理过程的控制。 使用各种 合成方法，包括我们开发的新程序，我们 制备了一系列氟取代的生物胺 各种环位置。 凭借其非常小的尺寸和高 电负性，氟是氢的非常有利的替代品 在这些类似物中。 这些物质的生物学特性和用途 环氟化生物胺已被证明是非常有价值的 并继续在众多研究中寻找应用，包括 运输、储存、释放、代谢机制研究， 以及这些胺的作用方式。 特别重要的是 发现6-氟去甲肾上腺素是一种选择性β-肾上腺素能药物 激动剂和2-氟去甲肾上腺素是一种选择性β-肾上腺素能药物 激动剂。 因为我们之前合成的 FNE 产生了外消旋体 材料，我们研究了纯 R-对映异构体的路线。 我们 研究了不对称氨基羟基化反应、对映选择性 Darzens 反应，以及使用手性路易斯酸催化羟醛 反应。 尽管已经获得了非外消旋产物，但还需要额外的 需要进行研究才能实现可接受的产量。 为了有 2-FNE 和 6-FNE 的可用替代生物前体，我们 先前合成的 threo-2- 和 6-氟二羟基-苯基丝氨酸 （氟-DOPS）的外消旋形式，但发现这些类似物效果很差 芳香族氨基酸脱羧酶的底物。 这可能是由于 通过 2R-异构体抑制 2S-异构体的脱羧作用 与应用于手性 FNE 的合成类似的策略，我们 研究纯手性 (2S,3R)-氟-DOPS 的路线。 氟化 制备了芳基乙炔胺并作为抑制剂进行了检查 多巴胺β-羟化酶。