SELECTIVE INHIBITORS OF BIOSYNTHESIS OF AMINERGIC NEUROTRANSMITTERS
SELECTIVE INHIBITORS OF BIOSYNTHESIS OF AMINERGIC NEUROTRANSMITTERS
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DOI：
10.1038/274906a0
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发表时间：
1978-01-01
期刊：
影响因子：
64.8
通讯作者：
ASTER, SD
中科院分区：
文献类型：
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作者：
KOLLONITSCH, J;PATCHETT, AA;ASTER, SD
尽管氨基酸的酶促脱羧对生物化学非常重要1，但很少有将活性与选择性结合起来的脱羧酶抑制剂。由氨基酸在体内脱羧形成的几种胺（生物胺）在生理学中具有关键作用。神经递质多巴胺、5-羟色胺、组胺和γ-氨基丁酸是由这种酶促脱羧作用产生的;多巴胺反过来又是去甲肾上腺素的前体2。儿茶酚胺参与血压的外周和中枢控制一直是许多研究的主题;例如，在自发性高血压大鼠研究的27个脑区中发现了升高的儿茶酚胺水平。具体而言，在与控制动脉血压有关的区域发现去甲肾上腺素和多巴胺水平升高3。广泛报道的精神分裂症的生化理论表明多巴胺能系统的紊乱是致病因素。4组胺水平升高被认为与过敏、超敏反应、胃溃疡和炎症等疾病有关5。鸟氨酸脱羧酶也是一个重要的抑制目标，因为它是多胺生物合成的初始酶，后者的水平增加与快速细胞分裂有关，包括肿瘤生长6。因此，这些关键酶的选择性抑制剂可能有助于阐明神经生理学和神经化学的复杂性，以及通过纠正这些激动剂的病理水平而在医学上提供服务。我们在此报告了氨基酸（C）转化为相应的取代的3-氟丙氨酸（B）的实例，产生了有效的时间依赖性脱羧酶灭活剂（表1）。此外，我们还制备了与这些脱羧酶的某些胺产物相对应的氟甲基衍生物（D），发现它们也是灭活剂（表1）。
ALTHOUGH the enzymatic decarboxylation of amino acids is of substantial importance to biochemistry1, there are few inhibitors of the decarboxylase enzymes which combine activity with selectivity. Several of the amines formed byin vivodecarboxylation of amino acids (biogenic amines) have key roles in physiology. The neurotransmitters dopamine, 5-hydroxytryptamine, histamine andγ-aminobutyric acid result from such enzymatic decarboxylation; dopamine in turn serves as the precursor of noradrenaline2. The involvement of catecholamines in peripheral and central control of blood pressure has been the subject of many investigations; for example, elevated catecholamine levels were found in some of the 27 brain regions investigated in spontaneously hypertensive rats. Specifically, elevated noradrenaline and dopamine levels were found in regions implicated in the control of arterial blood pressure3. A widely reported biochemical theory of schizophrenia suggests disturbance of the dopaminergic system as the causative factor.4Elevated histamine levels are believed to be involved in such diseases as allergy, hypersensitivity, gastric ulcer and inflammation5. Ornithine decarboxylase is also an important target for inhibition, as it is the initial enzyme in the biosynthesis of polyamines and increased levels of the latter have been associated with rapid cell division, including tumour growth6. Thus, selective inhibitors of these key enzymes could be of help in elucidating the complexities of neurophysiology and neurochemistry, as well as of service in medicine by correcting pathological levels of these agonists. We report here examples of the transformation of amino acids (C) into the corresponding substituted 3-fluoro-alanines (B), resulting in potent time-dependent decarboxylase inactivators (Table 1). In addition, we have prepared the fluoromethyl derivatives (D) corresponding to some of the amine products of these decarboxylases and find them also to be inactivators (Table 1).