Catechol-O-methyl transferase inhibitor

Category Catechol-O-methyl transferase inhibitor Half-life 2.4 hours... 

EMLA - local anaesthetic combination of lidocaine and prilocaine Entacapone - catechol-o-methyl transferase inhibitor Parkinson s disease Enoxaparin - low molecular weight heparin thrombosis prophylaxis prior to surgery Epoetin - erythropoietin replacement anaemia Erythromycin - antibiotic... 

Lotta, T., Taskinen, J., Backstrom, R. and Nissinen, E. (1992) PLS modelling of structure-activity relationships of catechol O-methyl-transferase inhibitors. J. Comput.-Aided Mol. Des. 6 253-272. 

Klatt P, Lamas S (2000) Regulation of protein function by S-glutathiolation in response to oxidative and nitrosative stress. Eur J Biochem 267(16) 4928-4944 Korlipara LV, Cooper JM, Schapira AH (2004) Differences in toxicity of the catechol-O-methyl transferase inhibitors, tolcapone and entacapone to cultured human neuroblastoma cells. Neuropharmacology 46(4) 562-569... 

Sun J, Von Tungeln LS, Hines W, Beger RD. Identification of metabolite profiles of the catechol-O-methyl transferase inhibitor tolcapone in rat urine using LC/MS-based metabonomics analysis. J Chromatogr B Anal Technol Biomed Life Sci 2009 877 2557-2565. 

Catechol-O-methyl transferase inhibitors [SED-15,1219 SEDA-32, 289 SEDA-33, 324]... 

Heizmsinn, P. Schmitt, M. Leube, J. Martin, H. Saner, A. Determination of the catechol-O-methyl-transferase inhibitor tolcapone and three of its metabolites in animal and humsm plasma smd urine by reversed-phase high-performance liquid chromatography with ultraviolet detection, J.Chromatogr.B, 1999, 730, 153-160. 

Mannisto PT, Kaakkola S (1999) Catechol-O-methyl-transferase (COMT). Biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 51 593-628... 

The deamination of DA to DOPAC can be prevented by MAOb inhibitors such as selegiline while COMT inhibitors stop its further o-methylation to HVA and the conversion of dopa to OMD. COMT inhibitors can act just peripherally (entacapone) or in the CNS as well (tolcapone). DD — dopa decarboxylase MAO—monoamine oxidase COMT—catechol-o-methyl transferase... 

Some biologically important o-quinones can react with the superoxide ion giving catechol derivatives, which may play a role in many diseases. For example, compounds bearing a nitro-catechol moiety have been claimed to be efficient catechol-0-methyl transferase inhibitors (Suzuki et al. 1992, Perez et al. 1992). The transferase is the first enzyme in the metabolism of catecholamine a hyperactivity of this enzyme leads to Parkinson s disease. Therefore, prediction of biological activity and antioxidant properties of quinones is an important challenge for researchers. 

A recently introduced class of drugs for the treatment of parkinsonism is the catechol-O-methyl transferase (COMT) inhibitors. COMT metabolizes catechol compounds, including dopamine and levodopa (see Chapter... 

Another approach to the therapy of Parkinson s disease involves the use of enzyme inhibitors. For example, inhibition of the enzyme monoamine oxidase B (MAO-B) by selegiline (4.105) improves the duration of L-DOPA therapy because it inhibits the breakdown of dopamine but not of NE. Likewise, inhibitors of catechol-O-methyl-transferase (COMT) can also be exploited as agents for the treatment of Parkinson s disease. L-DOPA and dopamine become inactivated by methylation the COMT enzyme responsible for this metabolic transformation can be clocked by agents such as entacapone (4.106) or tolcapone (4.107), allowing higher levels of L-DOPA and dopamine to be achieved in the corpus striamm of the brain. 

Tolcapone (Fig. 1.3) was designed as an inhibitor of the enzyme catechol O-methyl-transferase, and is useful in the L-DOPA treatment of Parkinson s disease [10]. In avoiding the methylation of L-DOPA as well as that of dopamine, it prolongs the beneficial activities of these molecules. 

Entacapone and tolcapone are peripheral inhibitors of catechol-O-methyl-transferase (COMT). COMT metabolises levodopa to an inactive product so their use enables greater amounts of levodopa to reach the brain. They are licensed for use as an adjunct to co-beneldopa and co-careldopa for patients who experience end-of-dose deterioration and cannot be stabilised on the combined preparations alone. 

Two Italian neurologists have described current theories about the pathophysiology of levodopa-associated motor fluctuations and the use of inhibitors of MAO type B, inhibitors of catechol-O-methyl transferase, and modi-fied-release levodopa in minimizing this problem (18). 

An interaction of ephedrine with entacapone, a specific, reversible, peripherally acting inhibitor of catechol-O-methyl transferase, has been reported (37). 

After five years of treatment about half of patients will experience the drug becoming less effective and a gradual recurrence of symptoms, especially hypokinesia, occurs. Another type of deterioration is the shortening of action of each dose with time ( end of dose deterioration ) and unpredictable fluctuations ( on-off effect ) in response to treatment, which can happen quite abmptly. It is not known why these effects occur, but they may be due to advance of the disease process. End of dose deterioration can be alleviated to a certain extent by the use of modified release preparations of levodopa or by the concurrent use of catechol-o-methyl transferase (COMT) inhibitors, for example enta-capone. COMT inhibitors prevent the peripheral breakdown of levodopa by an enzyme, COMT. 

Bonifacio, M. J., Palma, P. N., Almeida, L. and Soares-da-Silva, P. S. Catechol-O-methyl-transferase and its inhibitors in Parkinson s disease. CNS Drug Rev 13 (2007) 352-379. 

The administration of pyrogallol, an inhibitor of catechol-0-methyl transferase, prolongs responses to catecholamines [14, 196, 269]. The effect of pyrogallol on endogenous levels of catecholamines is doubtful [56, 117, 134, 137]. When U-0521 [90], another inhibitor of catechol-O-methyl transferase, was given to rats, the activity of this enzyme in liver, brain, uterus, and heart was reduced [91]. 

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