L-DOPA: From a biologically inactive amino acid to a successful therapeutic agent
L-DOPA: From a biologically inactive amino acid to a successful therapeutic agent
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DOI：
10.1007/s00726-001-0111-9
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发表时间：
2002-01-01
期刊：
影响因子：
3.5
通讯作者：
Hornykiewicz, O
中科院分区：
文献类型：
--
作者：
Hornykiewicz, O
本文追溯了天然氨基酸L-3，4-二羟基苯丙氨酸（L-dopa）的研究进展，从1911年首次合成其D，L外消旋体，从蚕豆幼苗中分离其L-异构体，到1961年该氨基酸作为治疗帕金森病（PD）的最有效药物的成功应用。在1913年从豆类中分离出来后，L-多巴被宣布为无生物活性。然而，1927年和1930年分别发表的两项早期药理学研究证明（在兔子身上）D，L-多巴对葡萄糖代谢（引起明显的高血糖症）和动脉血压有显著影响。在1938年发现了左旋多巴脱羧酶，并证明在动物和人体中左旋多巴可以酶促转化为多巴胺（DA），这是组织中儿茶酚胺生物合成链中第一个具有生物活性的胺之后，人们对左旋多巴生物活性的兴趣大大增加。这促使，在20世纪40年代，许多研究，无论是在动物和人类，特别关注的血管加压潜力的L-多巴/DA。在20世纪50年代，L-多巴研究的重点转移到其潜力补充实验耗尽（胰岛素或利血平）外周和脑儿茶酚胺存储和正常功能的伴随恢复。在此期间，特别感兴趣的是观察到左旋多巴逆转利血平诱导的“镇静”状态，其脱羧产物DA在动物和人脑中大量存在，优先定位于基底神经节。这些观察结果为PD脑中DA研究的开始奠定了基础。在1960年，发现了严重的脑DA缺陷，仅限于PD患者，一年后，左旋多巴在PD患者中的强大治疗效果得到了证实。1967年，慢性大剂量口服左旋多巴方案成功地引入临床实践。尽管最初对左旋多巴在PD中的作用机制存在一些疑问，但现在普遍认为左旋多巴在PD中的使用是脑神经递质替代疗法的经典例子。然而，L-多巴的DA替代潜力可能不是其唯一的作用，最近的证据表明，L-多巴在CNS中也可能具有独立于DA的生物活性。
The article traces the development of research on the naturally occurring amino acid L-3,4-dihydroxyphenylalanine (L-dopa), from the first synthesis of its D,L racemate in 1911, and the isolation of its L-isomer from seedling of Vicia faba beans to the amino acid's successful application, from 1961 onward, as the most efficacious drug treatment of Parkinson's disease (PD). Upon its isolation from legumes in 1913, L-dopa was declared to be biologically inactive. However, two early pharmacological studies, published in 1927 and 1930 respectively, proved (in the rabbit) that D,L-dopa exerted significant effects on glucose metabolism (causing marked hyperglycemia) and on arterial blood pressure. Interest in L-dopa's biological activity increased considerably following the discovery, in 1938, of the enzyme L-dopa decarboxylase and the demonstration that in the animal and human body L-dopa was enzymatically converted to dopamine (DA), the first biologically active amine in the biosynthetic chain of tissue catecholamines. This prompted, in the 1940s, many studies, both in animals and in humans, especially concerned with the vasopressor potential of L-dopa/DA. In the 1950s, the focus of L-dopa research shifted to its potential for replenishing the experimentally depleted (by insulin or reserpine) peripheral and brain catecholamine stores and the concomitant restoration of normal function. During that period, of special interest were the observations that L-dopa reversed the reserpine-induced state of "tranquilisation" and that its decarboxylation product DA occurred in high amounts in animal and human brain, with a preferential localization in the basal ganglia. These observations set the stage for the beginning of DA studies in PD brain. In 1960, the severe brain DA deficit, confined to patients with PD was discovered, and a year later L-dopa's strong therapeutic effect in patients with PD was demonstrated. In 1967, the chronic high-dose oral L-dopa regimen was successfully introduced into clinical practice. Despite some initial doubts about L-dopa's mechanism of action in PD, it is now generally recognized that L-dopa use in PD is a classic example of a brain neurotransmitter replacement therapy. However, the DA replacement potential of L-dopa may not be its sole action of interest, as suggested by recent evidence that L-dopa may also have its own biological activity in the CNS, independent of DA.