UMLS:C0030567 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of catechol-O-methyltransferase (COMT; EC 2.1.1.6) is a new therapeutic strategy in the treatment of Parkinson's disease. However, nothing is known about the effects of COMT inhibition on levodopa (L-dopa)-induced toxicity in dopamine (DA) neurons. Therefore we evaluated the effects of the selective COMT inhibitors Ro 41-0960, OR-486, and tolcapone alone and in combination with L-dopa in primary mesencephalic cultures from rat. Neither COMT inhibitor affected the growth of tyrosine hydroxylase immunoreactive (THir) cells with concentrations up to 10 microM when studied alone. However, Ro 41-0960 reduced the L-dopa-induced THir cell loss after 24 h in a dose-dependent manner, shifting the TD(50) value from 21 microM in the absence to 71 microM in the presence of 1 microM Ro 41-0960 (P <.01) without affecting survival of non-DA neurons. OR-486 and the clinically used COMT inhibitor tolcapone showed similar effects. In contrast, toxicity induced by D-dopa was not altered by COMT inhibitors. Furthermore, the primary metabolite of L-dopa formed by COMT, 3-O-methyldopa, and the methyl group donor S-adenosyl-L-methionine used by COMT did not alter THir neuron survival and L-dopa-induced toxicity, respectively, with concentrations up to 100 microM. These data demonstrate that COMT inhibition attenuates L-dopa toxicity toward DA neurons in vitro, but probably not by preventing 3-O-methyldopa production or cellular S-adenosyl-L-methionine depletion.
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PMID:Catechol-O-methyltransferase inhibition attenuates levodopa toxicity in mesencephalic dopamine neurons. 1069

Parkinson's disease (PD) is characterized by pathological changes which include degeneration of dopaminergic neurons in the substantia nigra pars compacta coupled with intracytoplasmic inclusions known as Lewy bodies. Neurodegeneration and Lewy bodies can also be found in the locus coeruleus, nucleus basalis, hypothalamus, cerebral cortex, cranial nerve motor nuclei, and central and peripheral components of the autonomic nervous system. PD progression is associated with the development of dementia, autonomic dysfunction, and postural instability, which do not respond well to conventional therapy. Therapeutic efforts aimed at preventing or at least delaying PD progression by reducing the overload of iron and generation of ROS, correcting the zinc deficiency may be of great benefit. Current pharmacotherapy of PD, in addition to symptomatic L-dopa treatment, includes the neuroprotective strategies with dopamine agonists, monoamine oxidase-B inhibitors (MAO-B), glutamate antagonists, catechol O-methyltransferase (COMT) inhibitors and other antioxidants or free radical scavengers. Depression, anxiety disorder and stress are all associated with PD and it is therefore necessary to include treatment regimens for these ailments in addition to the traditional pharmacotherapy for the symptoms of PD, as well as the neuroprotective measures noted above, in order to ensure the greatest possible benefit to PD patients.
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PMID:Importance of treatment of depression in assuring the most efficacious management of Parkinson's disease. 1090 82

Molecular mechanisms determining the turn-over rate and specificity of catechol O-methylation were studied by combining enzyme kinetic measurements, computational modeling of substrate properties and fitting ligands in a 3D model of the active site of the enzyme. Enzyme kinetic measurements were carried out for 46 compounds, including most clinically used catechol drugs, by using recombinant human soluble catechol O-methyltransferase (COMT). The most important mechanism decreasing the turnover rate and increasing affinity was the electron withdrawing effect of substituents. Several other mechanisms by which substituents affected reactivity and affinity were identified. Highest turnover rates were determined for unsubstituted catechol and pyrogallol. Pyrogallol derivatives generally seemed to be more specific substrates than catechols. Catecholestrogens were the most specific endogenous substrates, whereas catecholamines were rather poor substrates. Among the catechol drugs used in the L-DOPA treatment of Parkinson's disease, the COMT inhibitors entacapone and tolcapone were not methylated, whereas the DOPA decarboxylase inhibitor benserazide was 15 times more specific substrate than L-DOPA, the target of COMT inhibition. The structure-activity relationships found allow the prediction of reactivity, affinity, and specificity with useful accuracy for catechols with a wide range of structures and properties. The knowledge can be used in the evaluation of metabolic interactions of endogenous catechols, drugs and dietary catechols, and in the designing of drugs with the catechol pharmacophore.
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PMID:Molecular mechanisms controlling the rate and specificity of catechol O-methylation by human soluble catechol O-methyltransferase. 1116 Aug 77

High nonphysiological doses of l-dopa are administered to Parkinson's disease (PD) patients, to replenish the depleted dopamine (DA). A large portion of the administered L-dopa and the newly formed DA undergoes methylation by reacting with S-adenosyl-L-methionine (SAM). In the process SAM, as well as L-dopa and DA, is utilized and great demands are placed on the transmethylation system. In this study we investigated whether L-dopa increases the transmethylation process by inducing methionine adenosyl transferase (MAT), the enzyme that produces SAM, and catechol-O-methyl transferase (COMT), the enzyme that transfers the methyl group from SAM to L-dopa and DA. Swiss Webster mice were injected with L-dopa, four times/day, for 1 to 16 days. Brain DA, 3-O-methyldopa (3-OMD), SAM, S-adenosylhomocysteine (SAH), MAT, and COMT were measured following a 24-h withdrawal period. An increase of 264% of brain DA occurred at days 2 and 3 after which it tapered to about 164% of control. The brain level of 3-OMD increased to 870% of the control. SAM was increased by 44% after the sixth day and SAH level was about double after the second day. After day 3, MAT activity was increased by about 35%. Western blot analysis showed that MAT is more clearly characterized in 10% mercaptoethanol reducing buffer in which 31.5-, 38- (beta), and 48-kDa (alpha1/alpha2) subunits were distinctly revealed. The induction of the 38-kDa and, more prominently, the 48-kDa subunits of MAT and the potential transactivator proteins of MAT, c-Jun/AP-1, was evident by day 6. The 31.5-kDa subunit was downregulated. COMT was detected as 24.7-, 30-, and 47.5-kDa bands in the brain, consistent with the membrane-bound COMT I (MB-COMT) and the dimeric COMT II. The 24.7- and the 30-kDa MB-COMT bands were induced in the brain by day 6 and peaked on day 9. The highlight of the study is the fact that L-dopa induces the enzymes MAT and COMT. In addition, the downturn in brain DA after the sixth day coincides with the increase in SAM and the 48-kDa MAT protein. Thus, during PD treatment with L-dopa the induction of MAT and COMT is likely to occur and in turn increase the methylation and reduction of L-dopa and DA that may help cause the tolerance or the wearing-off effect developed to L-dopa.
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PMID:L-dopa upregulates the expression and activities of methionine adenosyl transferase and catechol-O-methyltransferase. 1152 Jan 27

Catechol-O-methyltransferase (COMT, EC 2.1.1.6) plays a central role in the metabolic inactivation of neurotransmitters and neuroactive xenobiotics possessing a catechol motif. 1-(3,4-Dihydroxy-5-nitrophenyl)-2-phenyl-ethanone (BIA 3-202) is a novel nitrocatechol-type inhibitor of COMT, the potential clinical benefit of which is currently being evaluated in the treatment of Parkinson's disease. In the present work we characterize the molecular interactions of BIA 3-202 within the active site of COMT and discuss their implication on the regioselectivity of metabolic O-methylation. Unrestrained flexible-docking simulations suggest that the solution structure of this complex is better described as an ensemble of alternative binding modes, in contrast to the well defined bound configuration revealed by the X-ray structures of related nitrocatechol inhibitors, co-crystallized with COMT. The docking results wherein presented are well supported by experimental evidence, where the pattern of in vitro enzymatic O-methylation and O-demethylation reactions are analyzed. We propose a plausible explanation for the paradoxical in vivo regioselectivity of O-methylation of BIA 3-202, as well as of its related COMT inhibitor tolcapone. Both compounds undergo in vivo O-methylation by COMT at either meta or para catechol hydroxyl groups. However, results herein presented suggest that, in a subsequent step, the p-O-methyl derivatives are selectively demethylated by a microsomal enzyme system. The overall balance is the accumulation of the m-O-methylated metabolites over the para-regioisomers. The implications for the general recognition of nitrocatechol-type inhibitors by COMT and the regioselectivity of their metabolic O-methylation are discussed.
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PMID:Molecular modeling and metabolic studies of the interaction of catechol-O-methyltransferase and a new nitrocatechol inhibitor. 1258 50

Catechol O-methyltransferase (COMT) inhibition has been proposed as a means to increase levodopa bioavailability in patients with Parkinson's disease, which may be useful in reducing the total dose of levodopa, diminishing its frequency of administration and, more importantly, improving fluctuations in the response to each individual dose of levodopa, which usually develop after chronic treatment. Entacapone is a potent, selective peripheral catechol O-methyltransferase inhibitor which effectively inhibits the O-methylation of levodopa, thus increasing its central bioavailability and potentiating its behavioral effects. In clinical trials in patients with Parkinson's disease, entacapone has prolonged and improved the therapeutic effect of levodopa combined with a dopa decarboxylase inhibitor. The new drug has increased the "on" time duration, decreased the "off" time duration and has reduced the total dose requirements of levodopa. Entacapone has shown optimal tolerability at the currently recommended doses, with the added benefit of a lower required dose of levodopa. This, in turn, improves the tolerability of levodopa and thus the overall tolerability of the treatment of advanced Parkinson's disease.
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PMID:Perspectives in the treatment of Parkinson's disease: COMT inhibitors open up new treatment strategies. 1297 67

BIA 3-202 is a novel catechol-O-methyltransferase (COMT) inhibitor being developed for use as a levodopa-sparing agent in Parkinson's disease. This study investigated the effect of four single oral doses of BIA 3-202 (50 mg, 100 mg, 200 mg, and 400 mg) compared with placebo on plasma concentrations of levodopa and its metabolite 3- O-methyl-levodopa (3-OMD) and on inhibition of erythrocyte COMT in healthy subjects receiving 100 mg of levodopa and 25 mg of benserazide (Madopar 125). This was a single-centre, double-blind, placebo-controlled, randomised, crossover study with five single-dose treatment periods. The washout period between doses was 2 weeks. On each treatment period, a different dose of BIA 3-202 or placebo was administered concomitantly with Madopar 125. Tolerability was assessed by recording adverse events, vital signs, continuous electrocardiogram and clinical laboratory parameters. In the study, 18 subjects (12 male and 6 female) participated. The drug combination was well tolerated. All doses of BIA 3-202 significantly increased the area under the concentration-time curve (AUC) versus placebo, ranging from 39% (95% confidence intervals, 1.06-1.69) with 50 mg to 80% (95% confidence intervals, 1.42-2.22) with 400 mg. No significant change in mean maximum plasma concentrations (C(max)) of levodopa was found. Mean C(max) and AUC of 3-OMD significantly decreased for all doses tested. BIA 3-202 caused a rapid and reversible inhibition of S-COMT activity, ranging from 57% (50 mg) to 84% (400 mg). In conclusion, the novel COMT inhibitor BIA 3-202 was well tolerated and significantly increased the bioavailability of levodopa and reduced the formation of 3-OMD when administered with standard release levodopa/benserazide.
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PMID:Pharmacokinetic-pharmacodynamic interaction between BIA 3-202, a novel COMT inhibitor, and levodopa/benserazide. 1451 7

1-methyl-4-phenyl-1,2,4,6,-tetrahydropyridine (MPTP) is a selective neurotoxin that produces striatal dopamine depletion resulting in parkinsonism like symptoms in humans and is, therefore, used to generate animal models for Parkinson's disease (PD). In this study, C57BL/6N mice were treated with MPTP acutely (3x20 mg/kg, 2-hour interval, one day injection). Mice were then sacrificed 24 hours after the last injection and brain tissue was collected for analysis. Significant decrease of striatal dopamine (DA) and the metabolites (DOPAC, HVA) was observed after MPTP treatment. MPTP also reduced protein expression of tyrosine hydroxylase (TH) in the striatum. Real time RT-PCR was used to examine selective genes of the dopaminergic system in the substantia nigra. Our data demonstrated that MPTP significantly decreased gene expression of TH, dopamine transporter (DAT), and vesicle monoamine transporter (VMAT), coinciding with the pattern of dopamine concentration changes and protein expression after MPTP treatment. Although a significant decrease of DA metabolites was observed in striatum, there was no change in the expression of monoamine oxidases (MAO-A, MAO-B) or catechol O-methyltransferase (COMT), indicating that these changes might be simply a consequence of reduced monoamine levels. In addition, gene expression of alpha-synuclein was also decreased with MPTP treatment, but there was no change in beta-synuclein and parkin. This is the first study using real-time PCR to indicate that MPTP selectively alters gene expression and provides information for clinical studies in PD. Future studies will focus on gene expression of other pathways that may be affected by MPTP treatment and investigation of gene expression in specific cell types in vivo using LCM technology.
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PMID:Selective alterations of gene expression in mice induced by MPTP. 1549 5

Inhibition of the enzyme catechol O-methyltransferase offers a therapeutic handle to regulate the catabolism of catecholamine neurotransmitters, providing valuable assistance in the treatment of CNS disorders such as Parkinson's disease. A series of ribose-modified bisubstrate inhibitors of COMT featuring 2'-deoxy-, 3'-deoxy-, 2'-aminodeoxy-3'-deoxy-, and 2'-deoxy-3'-aminodeoxyribose-derived central moieties and analogues containing the carbocyclic skeleton of the natural product aristeromycin were synthesized and evaluated to investigate the molecular recognition properties of the ribose binding site in the enzyme. Key synthetic intermediates in the ribose-derived series were obtained by deoxygenative [1,2]-hydride shift rearrangement of adenosine derivatives; highlights in the synthesis of carbocyclic aristeromycin analogues include a diastereoselective cyclopropanation step and nucleobase introduction with a modified Mitsunobu protocol. In vitro biological evaluation and kinetic studies revealed dramatic effects of the ribose modification on binding affinity: 3'-deoxygenation of the ribose gave potent inhibitors (IC50 values in the nanomolar range), which stands in sharp contrast to the remarkable decrease in potency observed for 2'-deoxy derivatives (IC50 values in the micromolar range). Aminodeoxy analogues were only weakly active, whereas the change of the tetrahydrofuran skeleton to a carbocycle unexpectedly led to a complete loss of biological activity. These results confirm that the ribose structural unit of the bisubstrate inhibitors of COMT is a key element of molecular recognition and that modifications thereof are delicate and may lead to surprises.
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PMID:Bisubstrate inhibitors of catechol O-methyltransferase (COMT): the crucial role of the ribose structural unit for inhibitor binding affinity. 1689 69

Parkinson's disease is a common neurodegenerative disorder that can cause significant disability and decreased quality of life. The cardinal physical signs of the disease are distal resting tremor, rigidity, bradykinesia, and asymmetric onset. Levodopa is the primary treatment for Parkinson's disease; however, its long-term use is limited by motor complications and drug-induced dyskinesia. Dopamine agonists are options for initial treatment and have been shown to delay the onset of motor complications. However, dopamine agonists are inferior to levodopa in controlling motor symptoms. After levodopa-related motor complications develop in advanced Parkinson's disease, it is beneficial to initiate adjuvant therapy with dopamine agonists, catechol O-methyltransferase inhibitors, or monoamine oxidase-B inhibitors. Deep brain stimulation of the subthalamic nucleus has been shown to ameliorate symptoms in patients with advanced disease. Depression, dementia, and psychosis are common psychiatric problems associated with Parkinson's disease. Psychosis is usually drug induced and can be managed initially by reducing antiparkinsonian medications. The judicious use of psychoactive agents may be necessary. Consultation with a subspecialist is often required.
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PMID:Parkinson's disease: diagnosis and treatment. 1955 11

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