Catechol-O-methyl transferase COMT inhibitors

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... 

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. 

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... 

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. 

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. 

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... 

A, adrenaline COMT, catechol-O-methyl transferase CSF, cerebrospinal fluid DA, 3,4-dihydroxyphenylethylamine (dopamine) Dopa, 3,4-dihydroxyphenylalanine 5HIAA, 5-hydroxyindoleacetic acid 5HT, 5-hydroxytryptamine (serotonin) 5HTP, 5-hydroxytryptophan HVA, 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid) MAO, monoamine oxidase MAOI, monoamine oxidase inhibitor MHPG,... 

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