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。使用各种合成方法，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各个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（6-FNE）是选择性α-肾上腺素能激动剂，2-氟诺啡肽（2-FNE）是选择性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观察到这种行为。 氟化DOPS和DOPAs。 在这项工作的最近扩展中，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6 F-L-苏型-DOPS），首先使用Evans对映选择性羟醛策略，最近使用有效的Sharpless不对称氨羟基化方法。我们研究了这些类似物作为多巴脱羧酶的底物。我们还完成了2-F-、5-F-、6-F-和2，6-diF-L-DOPA的对映选择性合成，以研究环取代对这些类似物的酶促脱羧速率的影响。氟取代对脱羧的主要影响与所有氟化类似物的Km增加有关（5-F > 2-F > 6-F >多巴）。这意味着在环位置2、5或6处的氟取代基的存在影响与活性位点的结合。相反，氟取代对脱羧的kcat的影响是最小的。因此，氟化类似物由于对酶的亲和力较低而被DDC脱羧效率较低。在类似物中，6-F-Dopa是最好的底物，kcat/Km约为L-Dopa的10%。[18 F] 6 F-L-DOPA已广泛用于PET研究，以量化多巴胺能功能，因此脱羧率是重要的考虑因素。 芳香族氨基酸脱羧酶将6-F-L-苏型-DOPS转化为R-6-FNE，但与磷酸吡哆醛辅因子竞争的Pictet Spengler环化降低了该过程的效率。使用2F-L-苏型-DOPS时，Pictet Spengler反应占主导地位，脱羧作用基本上被阻断。我们计划使用这一观察结果，氟在2-位促进Pictet Spengler环化开发探针的研究四氢异喹啉之间的生物胺和生物醛的形成。 侧链氟化胺和氨基酸。 我们以前制备的环氟化咪唑也是非常有价值的生物化学和药理学试剂。我们现在已经开发了合成侧链氟化的生物学上重要的咪唑，包括β-氟-和β，β-二氟组胺，β-氟尿刊酸，和α，β-二氟尿刊酸。我们将其扩展到相应的组氨酸衍生物和组氨酸的生物合成前体。氟代顺式尿刊酸被用来研究顺式尿刊酸介导的光免疫抑制机制。我们还制备了β，β-二氟色胺，包括β，β-二氟褪黑素。研究包括使用这些类似物作为色胺N-乙酰转移酶的机械探针。目前正在制定相应的解决办法。 MAO抑制剂。 几种重要的代谢酶单胺氧化酶（MAO）的抑制剂（一些在医学上有效）含有氟，这是抑制机制的重要特征。其他抑制剂含有环丙烷用于相同目的。我们已经制备并正在研究一系列在侧链中引入氟化环丙基的苄胺和苯乙胺作为新的MAO抑制剂，以确定这两种结构基序的综合作用。

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. Fluorinated DOPS and DOPAs. 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. We examined these analogues as substrates for dopa decarboxylase. We also completed 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. The predominant influence of fluorine substitution on decarboxylation is related to an increase in Km for all fluorinated analogues (5-F > 2-F > 6-F > Dopa). This implies that the presence of fluorine substituents at ring position 2, 5 or 6 affects binding to the active site. In contrast, the effects of fluorine substitution on the kcat for decarboxylation are minimal. Thus, the fluorinated analogues are decarboxylated less efficiently by DDC as a result of lower affinity for the enzyme. Of the analogues, 6-F-Dopa is the best substrate, with a kcat/Km some 10% that of L-Dopa. [18F]6F-L-DOPA has been used extensively in PET studies to quantify dopaminergic function, and rates of decarboxylation are thus important considerations. 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. We plan to use this observation that fluorine in the 2-position facilitates Pictet Spengler cyclization to develop probes for the study of tetrahydroisoquinoline formation between biogenic amines and biogenic aldehydes. Side-chain fluorinated amines and amino acids. 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, beta-fluorourocanic acid, and alpha,beta-difluorourocanic 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. We also prepared beta,beta-difluorotryptamines, including beta,beta-difluoromelatonin. Studies include the use of these analogues as mechanistic probes of tryptamine N-acetyltransferase. Approaches to the corresponding tryptophans are being developed. MAO Inhibitors. 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.