The O-methylated derivative of l-DOPA, 3- O-methyl- l-DOPA, fails to inhibit neuronal and non-neuronal aromatic l-amino acid decarboxylase (original) (raw)
Related papers
Biochemical Pharmacology, 1979
I!1 dro. z-acetylenic DOPA (RMI 7 1.858) is a potent inhibitor of aromatic I.-amino acid decarboxylase (AADC). Inhibition appears to consist of both a competitive. with a Ki of 0.3 PM. and an irreversible component. the enzyme losing 50 per cent ofits activity in 2Omin at an inhibitor concentration of IOOpM. After inhibition. the activity can only be partially restored by dialysis. z-Vinyl DOPA (RMI 7 1.8 16) is a less potent inhibitor of the enzyme. with a K, of 39 FM. No transformation of the inhibitors by AADC can be detected in the incubation medium. EX riro. both compounds (lO(r500 mg/kg. i.p.) reduce the activity of AADC in different organs. with a more pronounced effect in peripheral tissues than in brain. In rich. r-acetylenic DOPA (IO-500 mg/kg. i.p.) inhibits the peripheral decarboxylation of 1 'H I r.-DOPA and 5-hydroxytrvptophan with a consequent short-lasting elevation of brain catecholamines and serotonin. Aromatic L-amino acid decarboxylase (E.C. 4.1.1.26) (AADC) is an enzyme essential for the biosynthesis of a number of biogenic amines in both the peripheral and central nervous systems. The enzyme is not normally rate-limiting but its inhibition can alter the metabolism of exogenously supplied substrates such as L-DOPA or L-5-hydroxytryptophan. Several inhibitors of this enzyme are known. e.g. L-z-methyl-r-hydrazino-3,4dhydroxy-phenyl-propionic acid (carbidopa) 111 and N-(D.r-seryl-N-(2.3.4 trihydroxybenzyl) hydrazine-HCI (benserazide) 12 1. These compounds are irreversible inhibitors of AADC. In viva. they show a marked selectivity for the enzyme in peripheral tissues over that of central nervous system. They have been used clinically in combination with L-DOPA for the treatment of Parkinson's disease. Since hydrazine derivatives inter, act with many pyridoxal phosphate-dependent enzymes, the available inhibitors are not entirely specific for AADC. Recently the synthesis of two new analogues of L-DOPA: a-acetylenic DOPA (RMI 7 1.858. r-ethynyl-3-hydroxytyrosine) and z-vinyl DOPA (RMI 7 1.8 16. r-vinyl-3-hydroxytyrosine) has been reported 13.41. This paper describes the in vitro and in vivo effects of these compounds on AADC.
Neuroscience Research, 2010
l-DOPA is the most widely used treatment for Parkinson's disease. The anti-parkinsonian and pro-dyskinetic actions of l-DOPA are widely attributed to its conversion, by the enzyme aromatic l-amino acid decarboxylase (AADC), to dopamine. We investigated the hypothesis that exogenous l-DOPA can induce behavioural effects without being converted to dopamine in the reserpine-treated rat-model of Parkinson's disease. A parkinsonian state was induced with reserpine (3 mg/kg s.c.). Eighteen hours later, the rats were administered l-DOPA plus the peripherally acting AADC inhibitor benserazide (25 mg/kg), with or without the centrally acting AADC inhibitor NSD1015 (100 mg/kg). l-DOPA/benserazide alone reversed reserpine-induced akinesia (4158 ± 1125 activity counts/6 h, cf vehicle 1327 ± 227). Addition of NSD1015 elicited hyperactive behaviour that was approximately 7-fold higher than l-DOPA/benserazide (35755 ± 5226, P < 0.001). The hyperactivity induced by l-DOPA and NSD1015 was reduced by the alpha2C antagonist rauwolscine (1 mg/kg) and the 5-HT2C agonist MK212 (5 mg/kg), but not by the D2 dopamine receptor antagonist remoxipride (3 mg/kg) or the D1 dopamine receptor antagonist SCH23390 (1 mg/kg). These data suggest that l-DOPA, or metabolites produced via routes not involving AADC, might be responsible for the generation of at least some l-DOPA actions in reserpine-treated rats.
Aromatic L-Amino Acid Decarboxylase Activity of Mouse Striatum Is Modulated via Dopamine Receptors
Journal of Neurochemistry, 1993
Aromatic L-amino acid decarboxylase (AAAD) activity is enhanced in the striatum of control and MPTPtreated mice after administration of a single dose of the dopamine receptor antagonists haloperidol, sulpiride, and SCH 23390. MPTP-treated mice appear more sensitive to the antagonists, i.e., respond earlier and to lower doses of antagonists than control mice. The rise of AAAD activity induced by the antagonists is prevented by pretreatment with cycloheximide. The apparent K , values for ~-3,4-dihydroxyphenylalanine (L-DOPA) and pyridoxal 5-phosphate appear unchanged after treatment with the antagonists. Increased AAAD activity was observed also after subchronic administration of dopamine receptor antagonists or treatment with reserpine. A single dose of a selective dopamine receptor agonists had no effect on AAAD activity. In contrast, administration of L-DOPA, quinpirole, or SKF 23390 for 7 days lowers AAAD activity in the striatum. We conclude that AAAD is modulated in striaturn via dopaminergic receptors.
A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats
Pharmaceutical Research, 2001
To study the PK interaction of L-dopa/benserazide in rats. Methods. Male rats received a single oral dose of 80 mg/kg L-dopa or 20 mg/kg benserazide or 80/20 mg/kg L-dopa/benserazide. Based on plasma concentrations the kinetics of L-dopa, 3-O-methyldopa (3-OMD), benserazide, and its metabolite Ro 04-5127 were characterized by noncompartmental analysis and a compartmental model where total L-dopa clearance was the sum of the clearances mediated by amino-acid-decarboxylase (AADC), catechol-O-methyltransferase and other enzymes. In the model Ro 04-5127 inhibited competitively the L-dopa clearance by AADC. Results. The coadministration of L-dopa/benserazide resulted in a major increase in systemic exposure to L-dopa and 3-OMD and a decrease in L-dopa clearance. The compartmental model allowed an adequate description of the observed L-dopa and 3-OMD concentrations in the absence and presence of benserazide. It had an advantage over noncompartmental analysis because it could describe the temporal change of inhibition and recovery of AADC. Conclusions. Our study is the first investigation where the kinetics of benserazide and Ro 04-5127 have been described by a compartmental model. The L-dopa/benserazide model allowed a mechanism-based view of the L-dopa/benserazide interaction and supports the hypothesis that Ro 04-5127 is the primary active metabolite of benserazide.
Naunyn-Schmiedeberg's Archives of Pharmacology, 1988
In this study, two ester pro-drugs of dopamine (DA) were synthesized and evaluated. These derivatives were the monobenzoyl (MBDA) and dibenzoyl (DBDA) esters of DA. MBDA was 300-fold and DBDA was 20,000-fold more lipophilic than DA itself. The half-lives of hydrolysis for MBDA and DBDA at physiologic pH and temperature were 15 and 420 rain respectively. These compounds were radiolabelled and their uptake into brain measured. 14C-DBDA penetrated the brain rapidly; 0.28% of the dose injected was taken up per gram of brain tissue at 5 min. However DBDA did not produce measurable increases in DA levels in the brain. ~4C-MBDA was found not to penetrate the brain. However, when MBDA was administered intracerebroventricularly (i.c.v.) to rats, it caused DOPAC levels to increase significantly both in the striatum and in the rest of the brain. The increase in the amount of DOPAC measured in the striatum was 3 to 10-fold greater than that seen in the rest of the brain. In rats that were pretreated with the MAO inhibitor, pargyline, MBDA given i. c.v. caused increases in DA levels in both the striatum and in the rest of the brain. The increased DA levels in striatum were considerably greater than those seen in the rest of the brain. From these results, it is inferred that MBDA is being hydrolyzed in vivo in the brain to form DA which is then taken up into dopaminergic neurons. Given this, it seems likely that an ester pro-drug of DA can be obtained that will have sufficient lipophilicity to penetrate the brain as well as a rate of hydrolysis that will produce increases in DA in the brain.
Effects ofl-DOPA on extracellular dopamine in striatum of normal and 6-hydroxydopamine-treated rats
Brain Research, 1990
In vivo microdialysis was used to examine the effect of L-3,4-dihydroxyphenylalanine (L-DOPA) administration upon dopamine (DA) in extraceUular fluid both in intact striatum and in striatum of rats treated with the catecholaminergic neurotoxin 6-hydroxydopamine (6-HDA). Basal extracellular levels of DA were not significantly altered by 6-HDA unless the DA content of striatal tissue was reduced to less than 20% of control. Peripheral aromatic amino acid decarboxylase (AADC) inhibition (RO4-4602, 50 mg/kg i.p.) followed by L-DOPA treatment (100 mg/kg i.p.) elevated extracellular DA in striatum of control rats from 37 _+ 5 to 68 _+ 11 pg/sample (n= 7; values corrected for recovery of the dialysis probe). In animals with severe bilateral depletions of DA in striatal tissue (mean depletion 87%; n = 6), L-DOPA increased extracellular DA in striatum from 8 +_ 3 to 266 _+ 60 pg/sample. In animals with large unilateral depletions of DA in striatal tissue (mean depletion 96%; n = 6), the increase in extracellular DA in striatum after L-DOPA was greater on the lesion side (from 7 _+ 4 to 245 + 67 pg/sample) than on the intact side (from 28 _+ 11 to 61 +_ 8 pg/sample). Animals with unilateral DA depletions showed contralateral circling behavior after L-DOPA. Increases in extracellular DA approaching the magnitude of those occurring in DA-depleted striata were observed when intact animals were treated with nomifensine (5 mg/kg i.p.; n --5), an inhibitor of high-affinity DA uptake, in addition to L-DOPA.
European Journal of Pharmacology, 1988
In order to further examine the likely origin of the dopamine (DA) metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), certain drugs known to release DA from different intraneuronal pools were tested for their effects on extracellular striatal DA and DOPAC levels by means of brain microdialysis in the halothane-anaesthetized rat. Amphetamine (10-6 and 10-3 M), nomifensine (10-5 M), potassium chloride (30 and 60 raM), methylphenidate (10-5 and 10 4 M) and tyramine (10-5 M), when added to the perfusion medium and administered locally into the striatum via the dialysis membrane, increased the level of DA in striatal perfusates during the 20 rain of application. In comparison, the level of DOPAC in the perfusates was decreased by both amphetamine (10-5 M) and potassium chloride (60 mM), but was not significantly changed by nomifensine, methylphenidate or tyramine. The effect of amphetamine (10 6 M) and nomifensine (10-5 M) on DA and DOPAC levels was further studied by administering the drugs over a longer period of time (3 × 20 min). Although both of these treatments produced a similar increase of DA, only amphetamine reduced the levels of DOPAC. DA (10-4 but not 10-5 M) increased the levels of DOPAC but this effect was also seen in DA-denervated animals. These data indicate that when the DA nerve terminal is exposed to drugs which release newly synthesized DA, DOPAC declines possibly because intraneuronal monoamine oxidase is deprived of its main substrate. We suggest that these findings support the hypothesis that a major portion of the DA metabolite, DOPAC, is derived from an intraneuronal pool of newly synthesized DA.
1 The present work was designed to examine the interference of L-3,4-dihydroxyphenylalanine (L-DOPA) on the cell inward transport of L-5-hydroxytryptophan (L-5-HTP) and on its decarboxylation by aromatic L-amino acid decarboxylase (AAAD) in rat isolated renal tubules. 2 The accumulation of both L-5-HTP and L-DOPA in renal tubules was found to occur through non-saturable and saturable mechanisms. The kinetics of the saturable component L-5-HTP and L-DOPA uptake in renal tubules were as follows: L-5-HTP, V, = 24.9 + 4.5 nmol mg-I protein h-1 and Km = 121 (95% confidence limits: 75, 193) gM (n = 5); L-DOPA, Vm, = 58.0 + 4.3 nmol mg-' protein h-' and Km = 135 (97, 188) pM (n = 5). When the saturation curve of L-5-HTP tubular uptake was performed in the presence of L-DOPA (250 gM), the maximal rate of accumulation of L-5-HTP in renal tubules was found to be markedly (P<0.01) reduced (Vma,,= 10.5+1.7 nmol mg-' protein h-', n=4); this was accompanied by a significant (P<0.05) increase in Km values (325 [199, 531] gM, n=4). 3 L-DOPA (50 to 2000 gM) was found to produce a concentration-dependent decrease (38% to 91% reduction) in the tubular uptake of 5-HTP; the Ki value (in 4uM) of L-DOPA for inhibition of L-5-HTP uptake was found to be 29.1 (13.8, 61.5) (n= 6). 4 At the highest concentration tested the organic anion inhibitor, probenecid (10 UM) produced no significant (P=0.09) changes in L-5-HTP and L-DOPA uptake (18% and 22% reduction, respectively). The organic cation inhibitor, cyanine 863 (1-ethyl-2-[1,4-dimethyl-2-phenyl-6-pyrimidinylidene)methyl]-quinolinium) produced a potent inhibitory effect on the tubular uptake of L-5-HTP (Ki=212 [35, 1289] nM, n=8), being slightly less effective against L-DOPA uptake (Ki=903 [584, 1396] nM, n=5). The cyanine derivatives 1,1-diethyl-2,4-cyanine (decynium 24) and 1,1-diethyl-2,2-cyanine (decynium 22) potently inhibited the tubular uptake of both L-5-HTP (K, = 100 [49, 204] and 120 [26, 561] nM, n = 4-6, respectively) and L-DOPA (Ki=100 [40, 290] and 415 [157, 1094] nM, n = 5, respectively). 5 The Vm,, and Km values for AAAD using L-DOPA as the substrate (Vm,, = 479.9 + 74.0 nmol mg-' protein h-'; Km = 2380 [1630, 3476] gM; n = 4) were both found to be significantly (P< 0.01) higher than those observed when using L-5-HTP (V, = 81.4+ 5.2 nmol mg-' protein h-', Km=97 [87, 107] gM, n = 10). The addition of 5 mM L-DOPA to the incubation medium reduced by 30% (P< 0.02) the maximal rate of decarboxylation of L-5-HTP (Vm. = 56.7+ 3.1 nmol mg-' protein h-', n = 10) and resulted in a significant (P< 0.05) increase in Km values (249 [228, 270] gM, n = 10). 6 The results presented suggest that L-5-HTP and L-DOPA are using the same transporter (most probably, the organic cation transporter) in order to be taken up into renal tubular cells; L-DOPA exerts a competitive type of inhibition upon the tubular uptake and decarboxylation of L-5-HTP. The decrease in the formation of 5-HT as induced by L-DOPA may also depend on a decrease in the rate of its decarboxylation by AAAD.