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: 6289758
• 负责人: KENNETH 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/6289758
• 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. These ring-fluorinated biogenic amines 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. Because our previous syntheses of FNEs produced racemic material, we have investigated routes to the pure R-enantiomers. Highly enantioselective carbonyl reductions of fuorinated chloroketone intermediates with chiral boron catalysts (chemzymes), followed by side-chain elaboration, have provided a route to R- and S-FNEs in good yield. Enantioselective cyanohydrin formation catalyzed by chiral salen catalysts, followed by reduction, is a second procedure we have developed. Using this approach, R- and S- of 2- and 6-FNE and 2- and 6-FEPI have been prepared. Receptor binding of were carried out to assess the effects of stereoisomerism on receptor selectivities. The results confirm that receptor selectivity is dependent on fluorine in the 2- or 6-position together with a benzylic hydroxyl group in the correct R-configuration. In order to have available alternate biological precursors for 2-FNE and 6-FNE, we previously synthesized threo-2- and 6- fluorodihydroxyphenylserine (fluoro-DOPS) in the racemic form, but found these analogues to be poor substrates for aromatic amino acid decarboxylase. We have prepared the 2S,3R-isomers of 6-fluoro DOPS using Evans enantioselective aldol strategy, and preparation of the 2- fluoro analog is in progress. Fluorinated analogs of purine and pyrimidine bases are being prepared as potential P-site phosphodiesterase inhibitors, and as potential NMR probes for DNA structure and function. Fluorinated metabolites of 6-fluoro- metatyrosine (FMT) have been prepared and are being used as standards in applications of F-18 labelled FMT in PET studies. - Fluorine, Adrenergic Agonists, Receptor Selectivity, Catecholamines, Chiral Syntheses

生物胺在神经传递、代谢和控制各种生理过程中起着关键作用。利用多种合成方法，包括我们开发的新方法，我们已经制备了一系列在不同环位置上具有氟取代的生物胺。这些环氟化生物胺继续在许多研究中找到应用，包括对这些胺的运输、储存、释放、代谢和作用模式的机制的研究。特别重要的是发现6-氟诺啡肽是一种选择性α-肾上腺素能激动剂，2-氟诺啡肽是一种选择性β-肾上腺素能激动剂。因为我们以前的FNE合成产生外消旋材料，我们已经研究了纯R-对映体的路线。高对映选择性羰基还原氟化氯酮中间体与手性硼催化剂（chemzymes），然后侧链的加工，提供了一种路线，R-和S-FNE在良好的产率。手性salen催化剂催化的对映选择性氰醇形成，然后还原，是我们开发的第二个程序。利用这种方法，已经制备了2-和6-FNE以及2-和6-FEPI的R-和S-。进行受体结合以评估立体异构对受体选择性的影响。结果证实，受体选择性取决于2-或6-位的氟以及正确R-构型的苄羟基。为了获得2-FNE和6-FNE的替代生物前体，我们先前合成了外消旋形式的苏型-2-和6-氟二羟基苯基丝氨酸（氟-DOPS），但发现这些类似物是芳香族氨基酸脱羧酶的不良底物。我们已经用Evans对映选择性醛醇缩合法合成了6-氟DOPS的2S，3R-异构体，2-氟类似物的合成正在进行中。嘌呤和嘧啶碱基的氟化类似物正被制备为潜在的P-位点磷酸二酯酶抑制剂，并作为潜在的DNA结构和功能的NMR探针。已经制备了6-氟-间酪氨酸（FMT）的氟化代谢物，并将其用作PET研究中F-18标记FMT应用的标准品。- 氟，肾上腺素能激动剂，受体选择性，儿茶酚胺，手性合成