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Organic & Biomolecular Chemistry Jun 2021l-Dopa (3,4-dihydroxyphenylalanine) is a chiral amino acid generated via biosynthesis from l-tyrosine in plants and some animals. The presence of multiple interacting... (Review)
Review
l-Dopa (3,4-dihydroxyphenylalanine) is a chiral amino acid generated via biosynthesis from l-tyrosine in plants and some animals. The presence of multiple interacting sites makes l-Dopa a multifunctional building block for the preparation of supramolecular materials. The possibility to form hydrogen bonds and the presence of the aromatic ring allow l-Dopa molecules to interact through a series of non-covalent interactions. The additional presence of the catechol moiety really makes this compound unique: not only does it have implications in the self-assembly process of Dopa itself and with other substrates, but also it highly increases the number of applications of the final material, since it works as an antioxidant, radical trapper, metal chelator, reducing agent and adhesive. l-Dopa and catechol containing derivatives have been extensively introduced inside both synthetic and natural polymers to obtain amazing functional materials. In this review we report the preparation of small peptides containing l-Dopa, focusing on the supramolecular materials that can be obtained with them, ranging from fibrils to fibres, gels, films and coatings, all having the different applications mentioned above and many others.
Topics: Levodopa
PubMed: 33978030
DOI: 10.1039/d1ob00378j -
Biochimica Et Biophysica Acta Sep 2016Dopamine replacement therapy by its precursor, L-3.4-dihydroxyphenylalanine (L-DOPA), has been the treatment of choice for Parkinson's disease. However, the possible... (Review)
Review
BACKGROUND
Dopamine replacement therapy by its precursor, L-3.4-dihydroxyphenylalanine (L-DOPA), has been the treatment of choice for Parkinson's disease. However, the possible contributory effect of L-DOPA therapy on the progression of Parkinson's disease mediated by the L-DOPA-induced toxic metabolites remains elusive.
SCOPE OF REVIEW
Prolong use of L-DOPA leads to behavioral impediments and instigate the generation of several toxic metabolites. One such metabolite is homocysteine, the level of which increases in the plasma of Parkinson's disease patients undergoing L-DOPA therapy, as well as in brain of animal models of the disease. In concoction with parkinsonian neurotoxins, Hcy exaggerates dopaminergic neurodegeneration, while its intranigral infusion has been demonstrated to decrease the dopamine level as well as causes dopaminergic neurodegeneration. Therefore, it can be propounded that elevated level of Hcy (hyperhomocysteinemia) is one of the underlying causes of L-DOPA-induced side-effects and aggravates the progressive nature of Parkinson's disease, which has been focused here. We have provided a conjectural discussion on the involvement of Hcy in L-DOPA-induced dyskinesia in Parkinson's disease.
CONCLUSION
Hyperhomocysteinemia as a result of prolonged L-DOPA therapy is the emerging cause of L-DOPA-induced behavioral abnormalities and progressive nature of Parkinson's disease.
GENERAL SIGNIFICANCE
This review highlights that hyperhomocysteinemia could be a putative contributor of the side-effects of chronic L-DOPA therapy because of its neurotoxic potency.
Topics: Animals; Antiparkinson Agents; Behavior, Animal; Brain; Dopamine; Humans; Hyperhomocysteinemia; Levodopa; Parkinson Disease
PubMed: 27318154
DOI: 10.1016/j.bbagen.2016.06.018 -
Trends in Pharmacological Sciences Apr 1993Since the 1960s, L-3,4-dihydroxyphenylalanine (L-dopa), a precursor of dopamine, has been thought to occur in the cytoplasm of catecholaminergic neurones. L-Dopa is... (Review)
Review
Since the 1960s, L-3,4-dihydroxyphenylalanine (L-dopa), a precursor of dopamine, has been thought to occur in the cytoplasm of catecholaminergic neurones. L-Dopa is traditionally believed to be an inert amino acid that exerts actions and effectiveness in Parkinson's disease via its conversion to dopamine by L-aromatic amino acid decarboxylase. In contrast to this generally accepted idea, Yoshimi Misu and Yoshio Goshima propose, in this Viewpoint article, that L-dopa itself is an endogenous neurotransmitter or neuromodulator in the CNS. This hypothesis is mainly based on the findings that L-dopa is released in a transmitter-like manner and that exogenously applied levodopa produces some responses.
Topics: Animals; Dihydroxyphenylalanine; Humans; Levodopa; Neurotransmitter Agents; Receptors, Cell Surface
PubMed: 8100096
DOI: 10.1016/0165-6147(93)90082-u -
Parkinsonism & Related Disorders Jan 2009Dopamine (DA) supplementation therapy by l-dopa for Parkinson's disease (PD) was established around 1970. The dose of l-dopa can be reduced by the combined... (Review)
Review
Dopamine (DA) supplementation therapy by l-dopa for Parkinson's disease (PD) was established around 1970. The dose of l-dopa can be reduced by the combined administration of inhibitors of peripheral l-amino acid decarboxylase (AADC), catechol O-methyltransferase (COMT), or monoamine oxidase B (MAO B). DA in the striatum may be produced from exogenously administered l-dopa by various AADC-containing cells, such as serotonin neurons. The long-term administration of l-dopa in PD patients may produce l-dopa-induced dyskinesia (LID), which may be due to chronic overstimulation of supersensitive DA D1 receptors. l-dopa may be used in combination with various new strategies such as gene therapy or transplantation in the future.
Topics: Antiparkinson Agents; History, 20th Century; History, 21st Century; Humans; Levodopa; Parkinson Disease
PubMed: 19131039
DOI: 10.1016/S1353-8020(09)70004-5 -
Current Topics in Medicinal Chemistry 2009L-DOPA is a di-hydroxy-phenyl, catecholamine precursor, amino acid, initially considered as an inert compound and now the key stone for the treatment of Parkinson's... (Review)
Review
L-DOPA is a di-hydroxy-phenyl, catecholamine precursor, amino acid, initially considered as an inert compound and now the key stone for the treatment of Parkinson's disease (PD) and some hereditary dystonias. L-DOPA, when administered to mammals, is rapidly metabolized to dopamine and 3-OM-DOPA, and its half-life in plasma is roughly 2 hours which has been considered the explanation for some of the L-DOPA related complications in PD. There have been, therefore, sophisticated methods of improving its pharmacokinetics by the association of decarboxylase and COMT inhibitors, slow release preparations and continuous infusions. In addition to its symptomatic effects, the impact of L-DOPA on the natural course of the disease is intriguing. By alleviating motor deficits, L-DOPA may improve health quality and life span in patients with PD, but there are neurotoxic and neurotrophic effects of L-DOPA which may produce long term effects on disease progression. These effects are dependent of the dose, the status of the metabolic pathways involved in catecholamine metabolism, the balance of free radicals and their scavengers and the function of glia. Finally, there is new data suggesting that L-DOPA may be not only a catecholamine precursor but also a neurotransmitter by itself of yet unknown function.
Topics: Animals; Antiparkinson Agents; Humans; Levodopa; Neurons; Parkinson Disease
PubMed: 19754400
DOI: No ID Found -
The Journal of Physiology Oct 2021In newborn rats, L-DOPA increases the occurrence of air-stepping activity without affecting movement characteristics. L-DOPA administration increases the spinal content...
KEY POINTS
In newborn rats, L-DOPA increases the occurrence of air-stepping activity without affecting movement characteristics. L-DOPA administration increases the spinal content of dopamine in a dose-dependent manner. Injection of 5-HTP increases the spinal serotonin content but does not trigger air-stepping. 5-HTP counteracts the pro-locomotor action of L-DOPA. Less dopamine and serotonin are synthesized when L-DOPA and 5-HTP are administered as a cocktail.
ABSTRACT
The catecholamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), is a well-established pharmacological agent for promoting locomotor action in vertebrates, including triggering air-stepping activities in the neonatal rat. Serotonin is also a well-known neuromodulator of the rodent spinal locomotor networks. Here, using kinematic analysis, we compared locomotor-related activities expressed by newborn rats in response to varying doses of L-DOPA and the serotonin precursor 5-hydroxytryptophan (5-HTP) administered separately or in combination. L-DOPA alone triggered episodes of air-stepping in a dose-dependent manner (25-100 mg/kg), notably determining the duration of locomotor episodes, but without affecting step cycle frequency or amplitude. In contrast, 5-HTP (25-150 mg/kg) was ineffective in instigating air-stepping, but altered episode durations of L-DOPA-induced air-stepping, and decreased locomotor cycle frequency. High performance liquid chromatography revealed that L-DOPA, which was undetectable in control conditions, accumulated in a dose-dependent manner in the lumbar spinal cord 30 min after its administration. This was paralleled by an increase in dopamine levels, whereas the spinal content of noradrenaline and serotonin remained unaffected. In the same way, the spinal levels of serotonin increased in parallel with the dose of 5-HTP without affecting the levels of dopamine and noradrenaline. When both precursors are administrated, they counteract each other for the production of serotonin and dopamine. Our data thus indicate for the first time that both L-DOPA and 5-HTP exert opposing neuromodulatory actions on air-stepping behaviour in the developing rat, and we speculate that competition for the production of dopamine and serotonin occurs when they are administered as a cocktail.
Topics: 5-Hydroxytryptophan; Animals; Animals, Newborn; Dopamine; Levodopa; Rats; Serotonin
PubMed: 34411301
DOI: 10.1113/JP281983 -
Current Medicinal Chemistry 2015L-3,4-Dihydroxyphenylalanine [2-amino-3-(3,4-dihydroxyphenyl) propanoic acid (L-DOPA) is a natural constituent of animal and plant tissue derived from post-translational... (Review)
Review
L-3,4-Dihydroxyphenylalanine [2-amino-3-(3,4-dihydroxyphenyl) propanoic acid (L-DOPA) is a natural constituent of animal and plant tissue derived from post-translational modification of the amino acid tyrosine. L-DOPA is modified during metabolism to catecholamine neurotransmitters, noradrenaline and adrenaline, which are characterized by different biological activities. L-DOPA has been the first drug of choice in the therapy of Parkinson's disease that is a progressive neurodegenerative disorder involving the loss of dopaminergic neurons of substantia nigra pars compacta. The social and economic impact of these diseases is very high due to the progressive aging of the population. This review focuses on the biological effect of LDOPA, as well as on the synthesis of L-DOPA derivatives and their application in central nervous system diseases. Among them, L-DOPA-containing peptides (L-DOPA-Pep) show important biological and pharmacological activities. For example, L-DOPA analogues of the alpha-factor interact with models of the G protein-coupled receptor, inhibit the oxidation of low-density lipoproteins, and are used for improving L-DOPA absorption in long-term treatment of Parkinson's disease and as skin moisturizer in cosmetic compositions. Moreover, L-DOPA residues in proteins provide reactive tools for the preparation of adhesives and coatings materials. Usually, L-DOPA-Pep is prepared by traditional liquid or solid state procedures starting from simple amino acids. Recently, selective side-chain modifications of pre-formed peptides have also been reported both for linear and branched peptides. Here, we describe the recent advances in the synthesis of L-DOPA and dopa-peptidomimetics and their biological and pharmacological activities, focusing the attention on new synthetic procedures and biological mechanism of actions.
Topics: Dopamine; Dopaminergic Neurons; Dyskinesias; Humans; Levodopa; Oxidative Stress; Parkinson Disease; Peptides; Peptidomimetics; Prodrugs
PubMed: 26112144
DOI: 10.2174/0929867322666150625095748 -
Neuroscience Research Sep 1995We have explored probable neurotransmitter roles of L-3,4-dihydroxyphenylalanine (L-DOPA) in baroreceptor reflex and blood pressure regulation in depressor sites of the... (Review)
Review
We have explored probable neurotransmitter roles of L-3,4-dihydroxyphenylalanine (L-DOPA) in baroreceptor reflex and blood pressure regulation in depressor sites of the nucleus tractus solitarii (NTS) and the caudal ventrolateral medulla (CVLM), and in pressor sites of the rostral ventrolateral medulla (RVLM) in anesthetized rats. During microdialysis of these three areas, the basal L-DOPA release is in part tetrodotoxin (TTX)-sensitive and Ca2(+)-dependent, high K+ Ca2(+)-dependently releases dL-DOPA. L-DOPA microinjected (10-300 ng) dose-dependently produces postsynaptic depressor responses in the NTS and CVLM and pressor responses in the RVLM, and a recognition site for L-DOPA functions tonically to activate depressor neurons in the NTS and CVLM and pressor neurons in the RVLM. It is highly probable that L-DOPA is a neurotransmitter of the baroreceptor afferents terminating in the NTS, which is based on further findings such as (1) antagonism by a competitive L-DOPA antagonist against depressor responses to aortic nerve stimulation, (2) TTX-sensitive L-DOPA release by aortic nerve stimulation, (3) abolition of baroreceptor-stimulated L-DOPA release by bilateral sino-aortic denervation and (4) decreases in tyrosine hydroxylase (TH)- and L-DOPA-immunoreactivities without modifications of dopamine- and DBH-immunoreactivities in the left NTS and ganglion nodosum 7 days after ipsilateral aortic nerve denervation peripheral to the ganglion. In the NTS, GABA tonically functions to inhibit via GABAA receptors L-DOPA release and depressor responses to L-DOPA, whereas L-DOPA induces GABA release. Impaired TTX-sensitive neuronal activity to release L-DOPA in the NTS and enhanced TTX-sensitive neuronal activity including a decrease in decarboxylation of L-DOPA to dopamine and an increase in sensitivity of the recognition site to L-DOPA in the RVLM are relevant to the maintenance of hypertension in spontaneously hypertensive rats. Decreases in the contents of L-DOPA in the right CVLM 10 days after electrical lesion of the ipsilateral NTS suggest a 'L-DOPAergic' and monosynaptic relay from the NTS to the CVLM. L-DOPA seems to play major roles as a neurotransmitter for baroreceptor reflex and blood pressure regulation in the lower brainstem of rats.
Topics: Animals; Blood Pressure; Brain Stem; Electric Stimulation; Heart Rate; Levodopa; Phenylephrine; Rats
PubMed: 8532212
DOI: 10.1016/0168-0102(95)00939-q -
Current Pharmaceutical Design 2011L-Dopa is the mainstay of Parkinson's disease therapy; this drug is usually administered orally, but it is extensively metabolized in the gastrointestinal tract, so that... (Review)
Review
L-Dopa is the mainstay of Parkinson's disease therapy; this drug is usually administered orally, but it is extensively metabolized in the gastrointestinal tract, so that relatively little arrives in the bloodstream as intact L-Dopa. The peripheral conversion of L-Dopa by amino acid decarboxylase to dopamine is responsible for the typical gastrointestinal and cardiovascular side effects. To minimize the conversion to dopamine outside the central nervous system, L-Dopa is usually given in combination with peripheral inhibitors of amino acid decarboxylase. In spite of that, other central nervous side effects such as dyskinesia, on-off phenomenon and end-of-dose deterioration still remain. The main factors responsible for the poor bioavailability are the drug's physical-chemical properties: low water and lipid solubility, resulting in unfavorable partition, and the high susceptibility to chemical and enzymatic degradation. Starting from these considerations the prodrug approach has been applied to L-Dopa in order to overcome its metabolism problems and to improve its bioavailability. The goal of this paper is to provide the reader with a critical overview on L-Dopa prodrugs here classified according to the nature of the main chemical modification on L-Dopa backbone that led to the formation of the desired derivative.
Topics: Animals; Drug Design; Humans; Levodopa; Molecular Structure; Parkinson Disease; Prodrugs; Structure-Activity Relationship
PubMed: 22074421
DOI: 10.2174/138161211798194495 -
International Journal of Molecular... Sep 2023L-DOPA, the precursor of catecholamines, exerts a pro-locomotor action in several vertebrate species, including newborn rats. Here, we tested the hypothesis that...
L-DOPA, the precursor of catecholamines, exerts a pro-locomotor action in several vertebrate species, including newborn rats. Here, we tested the hypothesis that decreasing the degradation of monoamines can promote the pro-locomotor action of a low, subthreshold dose of L-DOPA in five-day-old rats. The activity of the degrading pathways involving monoamine oxidases or catechol-O-methyltransferase was impaired by injecting nialamide or tolcapone, respectively. At this early post-natal stage, the capacity of the drugs to trigger locomotion was investigated by monitoring the air-stepping activity expressed by the animals suspended in a harness above the ground. We show that nialamide (100 mg/kg) or tolcapone (100 mg/kg), without effect on their own promotes maximal expression of air-stepping sequences in the presence of a sub-effective dose of L-DOPA (25 mg/kg). Tissue measurements of monoamines (dopamine, noradrenaline, serotonin and some of their metabolites) in the cervical and lumbar spinal cord confirmed the regional efficacy of each inhibitor toward their respective enzyme. Our experiments support the idea that the raise of monoamines boost L-DOPA's locomotor action. Considering that both inhibitors differently altered the spinal monoamines levels in response to L-DOPA, our data also suggest that maximal locomotor response can be reached with different monoamines environment.
Topics: Rats; Animals; Levodopa; Tolcapone; Animals, Newborn; Catechol O-Methyltransferase; Nialamide; Locomotion
PubMed: 37834195
DOI: 10.3390/ijms241914747