HALOGENATED BIOGENIC AMINES IN BIOCHEMISTRY AND PHARMACOLOGY

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。使用多种合成方法，包括我们开发的新程序，我们已经制备了一系列在不同环位置取代氟的生物胺。这些环氟生物胺继续在许多研究中得到应用，包括对这些胺的运输、储存、释放、代谢和作用方式的机制的研究。特别重要的是发现6-氟肾上腺素是一种选择性α -肾上腺素能激动剂，2-氟肾上腺素是一种选择性β -肾上腺素能激动剂。由于我们之前的FNEs合成产生了外消旋物质，我们已经研究了获得纯r -对映体的途径。用手性硼催化剂（化学酶）对氟化氯酮中间体进行高对映选择性羰基还原，然后进行侧链精化，提供了一条产率高的R-和s - fne的途径。由手性salen催化剂催化的对映选择性氰丙烷形成，然后是还原，是我们开发的第二个程序。用这种方法制备了2-和6-FNE的R-和S-以及2-和6-FEPI。通过受体结合来评估立体异构体对受体选择性的影响。结果证实，受体的选择性取决于氟在2-或6-位置上与正确的r构型的苯基羟基一起。为了获得2-FNE和6- fne的替代生物前体，我们之前以外消旋形式合成了3 -2-和6-氟二羟基苯基丝氨酸（fluoro-DOPS），但发现这些类似物对于芳香氨基酸脱羧酶来说是很差的底物。我们利用Evans对映选择性醛醇策略制备了6-氟DOPS的2S、3r异构体，2-氟类似物的制备正在进行中。嘌呤和嘧啶碱基的氟化类似物正被制备成潜在的p位点磷酸二酯酶抑制剂，以及潜在的DNA结构和功能的核磁共振探针。已经制备了6-氟-甲基酪氨酸（FMT）的氟化代谢物，并将其作为F-18标记的FMT在PET研究中的应用标准。-氟，肾上腺素能激动剂，受体选择性，儿茶酚胺，手性合成

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