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: 6432100
• 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/6432100
• 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 these 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, even thought the R-enantiomers had no greater net selectivity than the racemic mixtures. 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 and 2-fluoro DOPS using Evans enantioselective aldol strategy. Sharpless asymmetric aminohydroxylation procedures are being investigated as more efficient approaches to these compounds. 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. 2-And 4-difluoromethylimidazole derivatives have been prepared to study the reactivities of side-chain fluorinated imidazoles. Efforts are directed toward synthesis of new side-chain fluorinated bioimdazles. Collaborative studies on development of enantioselective fluorinating agents continue.

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。利用各种合成方法，包括我们开发的新方法，我们制备了一系列在不同环位上进行氟取代的生物胺。这些环氟化生物胺继续在大量研究中得到应用，包括对这些胺的运输、储存、释放、代谢和作用模式的研究。特别重要的是发现6-氟肾上腺素是一种选择性的α-肾上腺素能激动剂，而2-氟肾上腺素是一种选择性的β-肾上腺素能激动剂。因为我们以前合成的FNE产生了外消旋物质，所以我们研究了合成纯R-对映体的路线。含氟氯酮中间体在手性硼催化剂(化学酶)上的高度对映选择性的羰基还原，以及随后的侧链精制，提供了一条高产率地合成R-和S-FNE的途径。手性Salen催化剂催化对映体选择性生成氰醇，然后还原，是我们开发的第二个步骤。用这种方法制备了2-和6-FNE和2-和6-FEPI的R-和S。这些受体的结合被用来评估立体异构体对受体选择性的影响。结果证实，受体的选择性依赖于2-位或6-位的氟以及正确的R-构型中的苄基羟基，即使R-对映体的净选择性并不比外消旋混合物高。为了获得可替代的2-FNE和6-FNE的生物前体，我们以前以外消旋的形式合成了苏氨酸-2-和6-氟二羟基苯丝氨酸(F-DOPS)，但发现这些类似物是芳香族氨基酸脱羧酶的不良底物。我们用Evans对映体选择性Aldol策略合成了6-氟DOPS和2-氟DOPS的2S，3R-异构体。夏普莱斯的不对称氨羟化反应被认为是合成这些化合物的更有效的方法。6-氟-偏酪氨酸(FMT)的氟代谢物已被制备出来，并被用作F-18标记的FMT在PET研究中的应用标准。合成了2-和4-二氟甲基咪唑类化合物来研究侧链含氟咪唑类化合物的反应活性。新的侧链含氟生物咪唑的合成是目前研究的热点。关于开发对映体选择性氟化剂的合作研究仍在继续。