Halogenated Biogenic Amines In Biochemistry And Pharmaco

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，我们最初以外消旋形式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（6-FNE）是一种选择性α -肾上腺素能激动剂，2-氟肾上腺素（2-FNE）是一种选择性β -肾上腺素能激动剂。氟化肾上腺素（FEPI）和其他苯乙醇胺激动剂也有这种行为。在最近的扩展工作中，我们制备了2-和6-FNE的R-和s -对映体以及2-和6-FEPI的R-和s -对映体。为了获得R-2-FNE和R-6-FNE的可替代生物前体，我们还制备了2-和6-氟二羟基苯基丝氨酸的2S， 3r异构体（2F-和6F-L-threo-DOPS），首先使用Evans对映选择性醛醇策略，最近使用高效的Sharpless不对称氨基羟基化程序。芳香族氨基酸脱羧酶将6- f - l - 3 - dops转化为R-6-FNE，但与吡哆醛磷酸辅因子竞争的Pictet Spengler环化降低了该过程的效率。对于2f - l - 3 - dops， Pictet - Spengler反应占主导地位，脱羧基本上被阻断。根据这一观察结果，我们开始了2- f -、5-F-、6-F-和2,6- dif - l - dopa的对映选择性合成，以研究环氟化对这些类似物酶促脱羧速率的影响。[18F]6F-L-DOPA在PET研究中被广泛用于量化多巴胺能功能，因此脱羧率是重要的考虑因素。初步结果表明，6- f -左旋多巴是一种非常有效的底物，其脱羧速度比左旋多巴快。

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 initially prepared in racemic form 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 (6-FNE) is a selective alpha-adrenergic agonist and 2-fluoronorepinephrine (2-FNE) is a selective beta-adrenergic agonist. This behavior also was seen with fluorinated epinephrines (FEPI) and other phenethanolamine agonists. In a recent extension of this work we prepared the R- and S-enantiomers of 2- and 6-FNE and the R- and S-enantiomers of 2- and 6-FEPI. In order to have available alternate biological precursors for R-2-FNE and R-6-FNE, we also prepared the 2S,3R-isomers of 2- and 6-fluoro-dihydroxyphenylserine (2F- and 6F-L-threo-DOPS), first using Evans enantioselective aldol strategy, and more recently using an efficient Sharpless asymmetric aminohydroxylation procedures. Aromatic amino acid decarboxylase converts 6-F-L-threo-DOPS to R-6-FNE, but a competing Pictet Spengler cyclization with the pyridoxal phosphate cofactor diminishes the efficiency of the process. With 2F-L-threo-DOPS, the Pictet Spengler reaction predominates and decarboxylation is essentially blocked. Prompted by this observation, we initiated enantioselective syntheses of 2-F-, 5-F-, 6-F-, and 2,6-diF-L-DOPA in order to study the effects of ring-fluorination on the rate of enzymatic decarboxylation of these analogues. [18F]6F-L-DOPA has been used extensively in PET studies to quantify dopaminergic function, and rates of decarboxylation are thus important considerations. Initial results indicate that 6-F-L-DOPA is a very effective substrate, and is decarboxylated more rapidly than L-DOPA. Ring-fluorinated imidazoles we previously prepared also have been very valuable as biochemical and pharmacological agents. We now have developed syntheses of side-chain fluorinated biologically important imidazoles, including beta-fluoro- and beta,beta-difluorohistamine, and beta-fluorourocanic acid. We are extending this to the corresponding histidine derivatives, and biosynthetic precursors of histidine. Fluorinated cis-urocanic acids are being used to study the mechanism of cis-urocanic acid-mediated photo-immunosuprression. Several inhibitors, some medicinally effective, of the important metabolic enzyme, monoamine oxidase (MAO), contain fluorine as an important feature that is critical to the inhibitory mechanism. Other inhibitors contain cyclopropane for the same purpose. We have prepared and are now studying a series of benzylamines and phenylethylamines that incorporate fluorinated cyclopropyl groups in the side chain as new MAO inhibitors to determine the combined effects of these two structural motifs.