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Experimental Neurology Aug 2008In Parkinson's disease patients, a prolonged half-life of dopamine formed from L-DOPA may reduce the risk of developing L-DOPA-induced side-effects. Deuterium...
In Parkinson's disease patients, a prolonged half-life of dopamine formed from L-DOPA may reduce the risk of developing L-DOPA-induced side-effects. Deuterium substitutions in the L-DOPA molecule are expected to yield dopamine with an altered half-life because C-D bonds are more stable than C-H bonds. Therefore we tested, in the rat, the neurochemical and behavioral effects of different types of L-DOPA with deuterium substitutions at the alpha-carbon and/or the beta-carbon. By means of microdialysis, we found that L-DOPA with 3 deuterium substitutions (D3-L-DOPA) enhanced dopamine output in the striatum more effectively than L-DOPA and all the other deuterium variants. Moreover, D3-L-DOPA produced a more pronounced stimulation of locomotor activity in reserpinized rats compared to conventional L-DOPA. In contrast beta,beta-D2-L-DOPA was less effective than L-DOPA in raising striatal dopamine levels and was ineffective at restoring locomotor activity in reserpinized rats. These results demonstrate that the introduction of deuterium at different positions in the L-DOPA molecule dramatically changes its behavioral and neurochemical profile and suggest that L-DOPA treatment of Parkinson's disease may be improved in this way.
Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Behavior, Animal; Brain Chemistry; Carbidopa; Deuterium; Dopamine; Dopamine Agents; Levodopa; Male; Microdialysis; Motor Activity; Rats; Rats, Wistar; Time Factors
PubMed: 18561915
DOI: 10.1016/j.expneurol.2008.05.003 -
Neurobiology of Aging Jan 2012Long-term L-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease (PD) is associated with motor complications such as dyskinesia. There are clear...
Long-term L-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease (PD) is associated with motor complications such as dyskinesia. There are clear functional interactions between dopaminergic and serotonergic type 2A receptors (5-HT(2A))-mediated neurotransmission. Moreover, 5-HT(2A) receptor antagonists can reduce L-DOPA-induced dyskinesia (LID). We hypothesized that enhanced 5-HT(2A)-mediated neurotransmission may be involved in the genesis of L-DOPA-induced dyskinesia. Radioligand binding autoradiography, using [(3)H]-ketanserin, was performed to define 5-HT(2A) receptor levels in brain tissue from macaques: 6 normal; 5 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned, parkinsonian macaques, without exposure to L-DOPA; 6 MPTP-lesioned, parkinsonian macaques, receiving a single administration of L-DOPA, and exhibiting no dyskinesia; and 6 MPTP-lesioned, parkinsonian, macaques chronically treated with L-DOPA, and exhibiting dyskinesia. 5-HT(2A) receptor binding was increased in the caudate, putamen, and middle layers of the motor cortex in chronically L-DOPA-treated animals, by 50%, 50%, and 45% respectively, compared with normal macaques. 5-HT(2A) binding was not significantly altered in parkinsonian, untreated, or parkinsonian, single treatment, nondyskinetic macaques, compared with normal. These data provide an anatomical basis for mechanisms to explain the efficacy of 5-HT(2A) antagonists against dyskinesia.
Topics: Animals; Autoradiography; Brain; Dyskinesia, Drug-Induced; Female; Levodopa; MPTP Poisoning; Macaca fascicularis; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Synaptic Transmission
PubMed: 20561716
DOI: 10.1016/j.neurobiolaging.2010.04.035 -
Journal of Neurology, Neurosurgery, and... Feb 1977It has been suggested that the therapeutic response to levodopa in patients with Parkinson's disease may be related to changes in plasma growth hormone concentration. In...
It has been suggested that the therapeutic response to levodopa in patients with Parkinson's disease may be related to changes in plasma growth hormone concentration. In order to examine this problem, we have determined plasma DOPA and growth hormone levels after a standard oral levodopa load in 32 patients with Parkinson's disease. Levodopa caused an increase in plasma growth hormone concentration in 30 subjects. The magnitude and timing of this growth hormone response was not related to the clinical response, the presence or absence of response swings, or the occurrence of dyskinesias. The growth hormone response to levodopa is normal in patients with Parkinson's disease and not altered by long-term levodopa treatment.
Topics: Adult; Aged; Dihydroxyphenylalanine; Dyskinesia, Drug-Induced; Female; Growth Hormone; Humans; Levodopa; Male; Middle Aged; Parkinson Disease
PubMed: 864480
DOI: 10.1136/jnnp.40.2.162 -
Neurologic Clinics May 1992The success of L-dopa therapy in patients with Parkinson's disease and the concepts discussed in this article are summarized in Figure 6. Even in advanced stages of... (Review)
Review
The success of L-dopa therapy in patients with Parkinson's disease and the concepts discussed in this article are summarized in Figure 6. Even in advanced stages of disease, 80% of parkinsonian disability remains responsive to L-dopa therapy. The 50% of the response contaminated by response fluctuations should be viewed, at least in part, as a hopeful sign that the system is still responding to L-dopa therapy. Unfortunately suboptimal control of response fluctuations is still a source of consternation for patient and treating physicians alike. Response fluctuations notwithstanding, it should be emphasized that patients actually do better at every stage of disease for having been on L-dopa, as recently confirmed in a retrospective study of the relationship between response fluctuations and the timing of initiation of therapy. To the extent that the increasing frequency, amplitude, and complexity of response fluctuations add to the overall parkinsonian disability, the phenomenon demands a better understanding that will hopefully lead to better corrective or preventive measures.
Topics: Corpus Striatum; Humans; Levodopa; Parkinson Disease; Receptors, Dopamine
PubMed: 1584186
DOI: No ID Found -
Carbohydrate Research Nov 2009Dopamine-HCl and L-DOPA-alpha-glycosides were prepared by reaction with cyclomaltohexaose, catalyzed by Bacillus macerans cyclomaltodextrin glucanyltransferase. The...
Dopamine-HCl and L-DOPA-alpha-glycosides were prepared by reaction with cyclomaltohexaose, catalyzed by Bacillus macerans cyclomaltodextrin glucanyltransferase. The reaction gave maltodextrins attached to dopamine and L-DOPA; the maltodextrins were trimmed by reactions with glucoamylase and beta-amylase to produce alpha-glucosyl- and alpha-maltosyl-glycosides, respectively. The glucoamylase- or beta-amylase-treated dopamine- and L-DOPA-alpha-glycosides were fractionated and purified by BioGel P-2 gel-filtration column chromatography and preparative descending paper chromatography. Analysis by MALDI-TOF mass spectrometry and one- and two-dimensional NMR showed that the purified glycosides of dopamine and L-DOPA were glycosylated at the hydroxyl groups of positions 3 and 4 of the catechol ring. The major product was found to be 4-O-alpha-glycopyranosyl L-DOPA, and it was shown to be more resistant to oxidative tolerance experiments, involving hydrogen peroxide and ferrous ion, than L-DOPA. L-DOPA-alpha-glycosides are possibly more effective substitutes for L-DOPA in treating Parkinson's disease in that they are more resistant to oxidation and methylation, which renders L-DOPA ineffective and deleterious.
Topics: Bacillus; Dopamine; Glucosyltransferases; Glycosides; Levodopa; Nuclear Magnetic Resonance, Biomolecular; Polysaccharides; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 19793583
DOI: 10.1016/j.carres.2009.06.041 -
Advances in Neurology 1987
Topics: Biotransformation; Carbidopa; Chromatography, High Pressure Liquid; Dihydroxyphenylalanine; Disability Evaluation; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Humans; Kinetics; Levodopa; Methyldopa; Parkinson Disease; Receptors, Dopamine; Receptors, Dopamine D2; Tiapamil Hydrochloride
PubMed: 2950730
DOI: No ID Found -
The Journal of Laboratory and Clinical... Jan 2000gamma-L-glutamyl-L-DOPA (gludopa) is a dopamine prodrug that is relatively specific for the kidney. Because dopamine is phosphaturic, the present study compared the...
gamma-L-glutamyl-L-DOPA (gludopa) is a dopamine prodrug that is relatively specific for the kidney. Because dopamine is phosphaturic, the present study compared the phosphaturic effects of the infusion of equimolar doses of gludopa (n = 8), L-DOPA (n = 8), and gamma-L-glutamyl-L-tyrosine (glutyrosine, n = 6). Glutyrosine was used as a control to evaluate the effect of the glutamyl portion of gludopa on phosphate excretion. Sprague-Dawley rats (350 to 400 g) were anesthetized with 5-sec-butylethyl-2-thyobarbituric acid (Inactin; 100 mg/kg, IP) and underwent thyroparathyroidectomy. Clearances were taken during the infusion of normal saline vehicle, followed by the infusion of gludopa, L-DOPA, or glutyrosine, all infused at the rate of 10 nmol/kg bolus and 0.8 nmol/kg/min (iv). To determine the contribution of glutamyl derivative to phosphate excretion, gludopa or L-DOPA was infused in the presence of SCH23390, a DA-1 receptor antagonist. Gludopa infusion significantly increased dopamine excretion (from 1.9+/-0.2 ng/min to 17.0+/-3.9 ng/min, delta15.0+/-3.9 ng/min, P < .008) and fractional excretion of phosphate (from 2.6%+/-0.6% to 34.8%+/-1.8%, delta32.0%+/-1.6%, P < .001). L-DOPA infusion significantly increased dopamine excretion (from 1.4+/- 0.4 ng/min to 9.7+/-1.6 ng/min, delta8.3+/-1.5 ng/min, P < .001) and fractional excretion of phosphate (from 1.7%+/-0.6% to 8.2%+/-2.0%, delta6.4%+/-1.5%, P < .004). Glutyrosine infusion significantly increased fractional excretion of phosphate (from 2.8%+/-0.8% to 17.5%+/-5.2%, delta14.6%+/-4.8%, P < .03) without changing dopamine excretion (delta0.5+/-0.2 ng/min). Infusion of gludopa in the presence of SCH23390 increased fractional excretion of phosphate (from 5.7%+/-2.5% to 12.6%+/-3.5%, delta6.8%+/-2.3%, n = 6, P < .03), whereas SCH23390 completely blocked the phosphaturic effect of L-DOPA. We conclude that gamma-L-glutamyl-L-DOPA is more phosphaturic than L-DOPA in the rat because of the combined effects of dopamine and the glutamyl moiety.
Topics: Animals; Benzazepines; Blood Pressure; Dihydroxyphenylalanine; Dipeptides; Dopamine Antagonists; Glomerular Filtration Rate; Injections, Intravenous; Kidney; Levodopa; Male; Phosphates; Rats; Rats, Sprague-Dawley
PubMed: 10638694
DOI: 10.1016/s0022-2143(00)70020-5 -
Biochemical Pharmacology Jun 1990In vivo double-label experiments in rats were designed to correlate the peripheral and cerebral metabolism of 6-[18F]fluoro-L-DOPA [( 18F]FDOPA) with that of [3H]L-DOPA.... (Comparative Study)
Comparative Study
In vivo double-label experiments in rats were designed to correlate the peripheral and cerebral metabolism of 6-[18F]fluoro-L-DOPA [( 18F]FDOPA) with that of [3H]L-DOPA. Authentic samples of the major [18F]FDOPA metabolites were synthesized to identify the 18F-labeled metabolites. After carbidopa pretreatment and intravenous administration of the compound, the products of peripheral metabolism in plasma were analyzed at times from 3 to 60 min. In the periphery, amine conjugates were detected but they accounted for less than 15% of the total radioactivity; the major metabolites were 3-O-methyl-6-[18F]fluoro-L-DOPA and 3-O-methyl-[3H]L-DOPA. The rate and extent of 3-O-methylation of [18F]FDOPA exceeded that of [3H]L-DOPA. Both 3-O-methylated products entered the striatum and cerebellum where they contributed significant but uniform activity. Analysis of cerebral metabolism in these structures indicated a linear accumulation of total radioactivity: a striatum/cerebellum ratio of 2 was observed by 60 min. 6-[18F]Fluorodopamine (35%) and [3H]dopamine (55%) were the major metabolites formed in the striatum: however, the methylated [18F]FDOPA and [3H]DOPA products of predominantly peripheral origin represented 55% (18F) and 35% (3H) of the total radioactivity respectively. Other [3H]dopamine metabolites and their 18F-labeled analogs represented less than 10-15% at all times analyzed. The cerebellum radioactivity was composed only of [18F]FDOPA, [3H]DOPA and their 3-O-methylated products. These data will serve as the basis for the development of kinetic models of [18F]FDOPA metabolism that can be applied to the evaluation of central dopamine biochemistry with positron emission tomography in humans.
Topics: Animals; Brain; Carbidopa; Chromatography, High Pressure Liquid; Dihydroxyphenylalanine; Fluorine Radioisotopes; Injections, Intravenous; Kinetics; Levodopa; Male; Rats; Rats, Inbred Strains; Tritium
PubMed: 2112915
DOI: 10.1016/0006-2952(90)90601-g -
Bioorganic & Medicinal Chemistry Letters Apr 2001A series of dimeric derivatives (+)-1, and (+)-2, and (+)-3a-d of L-Dopa diacetyl esters was synthesized and evaluated as potential L-Dopa prodrugs with improved...
A series of dimeric derivatives (+)-1, and (+)-2, and (+)-3a-d of L-Dopa diacetyl esters was synthesized and evaluated as potential L-Dopa prodrugs with improved physicochemical properties. All the new compounds showed chemical stability in aqueous buffer solutions (pH 1.3 and 7.4). A relatively slow release of L-Dopa in human plasma was observed.
Topics: Animals; Dimerization; Drug Stability; Half-Life; Humans; Hydrogen-Ion Concentration; Hydrolysis; Levodopa; Plasma; Prodrugs; Rats
PubMed: 11327596
DOI: 10.1016/s0960-894x(01)00140-8 -
Life Sciences 1997We have proposed that L-3,4-dihydroxyphenylalanine (L-DOPA) is a neurotransmitter and/or neuromodulator in the central nervous system (1). In this study, we investigated...
We have proposed that L-3,4-dihydroxyphenylalanine (L-DOPA) is a neurotransmitter and/or neuromodulator in the central nervous system (1). In this study, we investigated whether or not L-threo-dihydroxyphenylserine (L-threo-DOPS), a synthetic amino acid structurally related to L-DOPA, microinjected into the caudal ventrolateral medulla (CVLM) and the rostral ventrolateral medulla (RVLM) shows cardiovascular actions similar to those of L-DOPA in anesthetized rats. When L-threo-DOPS was microinjected into CVLM, it produced dose-dependent (0.01-3 ng) depressor and bradycardic responses. D-threo-DOPS (3 ng) produced no effect. The responses to L-threo-DOPS (1 ng) were almost completely blocked by L-DOPA methyl ester (1 microg), a competitive antagonist for L-DOPA, supporting the existence of an L-threo-DOPS-sensitive recognition site for L-DOPA in CVLM. Microinjection of L-threo-DOPS into RVLM, however, showed no effect (0.001-100 ng), which contrasted with the cardiopressor action of L-DOPA applied in RVLM. In RVLM, there may exist an L-threo-DOPS-insensitive recognition site for L-DOPA.
Topics: Animals; Blood Pressure; Dose-Response Relationship, Drug; Droxidopa; Glutamic Acid; Heart Rate; Levodopa; Male; Medulla Oblongata; Microinjections; Organ Specificity; Rats; Rats, Wistar
PubMed: 9315508
DOI: 10.1016/s0024-3205(97)00659-0