COMT inhibitors

Early COMT inhibitors, like gallates, tropolone and U-0521 (3, 4 -dihydroxy-2-methyl-propiophenone) have IC50 and IQ values in the micromolar range or higher but may still be practical in vitro tools. However, owing to unfavourable pharmacokinetics and toxicity their clinical use is not possible [1]. 

Second generation COMT inhibitors were developed by three laboratories in the late 1980s. Apart from CGP 28014, nitrocatechol is the key structure of the majority of these molecules (Fig. 3). The current COMT inhibitors can be classified as follows (i) mainly peripherally acting nitrocatechol-type compounds (entacapone, nitecapone, BIA 3-202), (ii) broad-spectrum nitrocatechols having activity both in peripheral tissues and the brain (tolcapone, Ro 41-0960, dinitrocatechol, vinylphenylk-etone), and (iii) atypical compounds, pyridine derivatives (CGP 28014,3-hydroxy-4-pyridone and its derivatives), some of which are not COMT inhibitors in vitro but inhibit catechol O-methylation by some other mechanism. The common features of the most new compounds are excellent potency, low toxicity and activity through oral administration. Their biochemical properties have been fairly well characterized. Most of these compounds have an excellent selectivity in that they do not affect any other enzymes studied [2,3]. 

The main clinical use of COMT inhibitors is as adjunct (or additional adjunct) in the therapy of Parkinson s disease. The standard therapy of Parkinson s disease is oral L-dopa (as a drug levodopa) given with a dopa decarboxylase (DDC) inhibitor (e.g. carbidopa and benserazide), which does not reach the brain. When the peripheral DDC is inhibited, the concentration of 3-O-methyldopa (3-OMD), a product of COMT, in plasma is many times that of L-dopa. Since the half-life of 3-OMD is about 15 h, compared to about 1 h for L-dopa, the concentration of 3-OMD remains particularly high during chronic therapy, especially if new slow release L-dopa preparations are used. A triple therapy (L-dopa plus DDC inhibitor plus COMT-inhibitor) will... 

COMT inhibitors rescue l-dopa and improve the brain entry of L-dopa by decreasing 3-OMD formation in peripheral tissues. The dose of L-dopa could be decreased, compared with the present combination therapy. Dose interval of L-dopa could also be prolonged. Further, COMT inhibitors should decrease fluctuations of dopamine formation in the brain. 

In patients having Parkinson s disease, both entacapone and tolcapone potentiate the therapeutic effect of L-dopa and prolong the daily ON time by 1-2 h. In the clinic, COMT inhibitors have been well tolerated, and the number of premature terminations has been low. In general, the incidence of adverse events has been higher in tolcapone-treated patients than in entacapone-treated patients. The main events have comprised of dopaminergic and gastrointestinal problems [2,3]. 

An additional benefit of COMT inhibitors can be found in positron emission tomography (PET) studies. In PET, using 6-[18F]-fluoro-L-dopa (6-FD) to visualize the brain dopamine metabolism, the peripheral formation of 3-0-methyl-6-[18F]-fluoro-L-dopa (3-OMFD) by COMT is harmful. 3-OMFD contaminates the brain radioactivity analysed since it is easily transported like 3-OMD to the... 

Mannisto PT, Kaakkola S (1989) New selective COMT inhibitors Usefi.il adjuncts for Parkinson s disease Trends Pharmacol Sci 10 54—56... 

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... 

Torn wall M, Mannisto PT (1993) The effect of three types of COMT inhibitors on L-dopa-induced circling behaviour in rats. Eur J Pharmacol 250 77-84... 

Guttman M, Leger G, Reches A, et al (1993) Administration of the new COMT inhibitor OR-611 increases striatal uptake of fluorodopa. Movement Disord 8 298-304... 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

A newer classification of antiparkinson drugs is the catechol-O-methyltransferase (COMT) inhibitors. Examples of the COMT inhibitors are entacapone (Comtan) and tolcapone (Tasmar). 

These drugs are thought to prolong the effect of levodopa by blocking an enzyme, catechol-O-methyltransferase (COMT), which eliminates dopamine. When given with levodopa, the COMT inhibitors increase the plasma concentrations and duration of action of levodopa... 

The COMT inhibitors are used as adjuncts to levodopa7 carbidopa in Fhrkinson s disease Tolcapone is a potent COMT inhibitor that easily crosses the blood-brain barrier. However, the drug is associated with liver damage... 

The adverse reactions most often associated with the administration of the COMT inhibitors include disorientation, confusion, light-headedness, dizziness, dyskinesias, hyperkinesias, nausea, vomiting, hallucinations, and fever. Other adverse reactions are orthostatic hypotension, sleep disorders, excessive dreaming, somnolence, and muscle cramps. A serious and possibly fatal adverse reaction that can occur with the administration of tolcapone is liver failure... 

These dm are contraindicated in patients with a hypersensitivity to the dragp and during pregnancy (Category C) and lactation. Tolcapone is contraindicated in patients with liver dysfunction. The COMT inhibitors are used with caution in patients with hypertension, hypotension, and decreased hepatic or renal function. 

The COMT inhibitors should not be administered with the monoamine oxidase (MAO) inhibitors (see Chap. 31) because there is an increased risk of toxicity. If the COMT inhibitors are administered with norepinephrine, dopamine, dobutamine, methyldopa, or epinephrine, there is a risk of increased heart rate, arrhythmias, and excessive blood pressure changes. 

COMT inhibitors Tokappne PyrgggllQi CacaiJiols — 0 NA — Veskulftr uptake inhibitors Reserpina... 

There is also some evidence for subtypes of COMT but this has not yet been exploited pharmacologically. Certainly, the majority of COMT is found as soluble enzyme in the cell cytosol but a small proportion of neuronal enzyme appears to be membrane bound. The functional distinction between these different sources of COMT is unknown. COMT inhibitors also exist (e.g. pyrogallol), mostly as catechol derivatives, but so far, most have proved to be highly toxic. Only recently have drugs been developed which are selective for COMT one of these agents, tolcapone, is used currently in treatment of Parkinson s disease (see Chapter 15). 

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... 

Levodopa is a better substrate for COMT than MAO and when given with an ExCDDI most of it is o-methylated to OMD (Fig. 15.4). Recently COMT inhibitors have been developed which act either just peripherally (entacopone) or centrally as well... 

Add other PD medications (dopamine agonist, selegiline, amantadine, or COMT inhibitor)... 

When additional relief is needed, the addition of levodopa (L-dopa) should be considered. With the development of motor fluctuations, addition of a catechol-O-methyltransferase (COMT) inhibitor should be considered to extend L-dopa duration of activity. 

L-dopa is not bound to plasma proteins, and the elimination half-life is about 1 hour. The addition ofcarbidopa can extend the half-life to 1.5 hours, and the addition of a COMT inhibitor (e.g., entacapone) can extend it to about 2 to 2.5 hours. 

A final pharmacological strategy for treatment of Parkinson s disease comes from enzyme inhibition. This was initally done with an MAO inhibitor, L-deprenyl (selegiline, Eldepryl), but more recent drugs have become available that are COMT inhibitors. L-Deprenyl is an inhibitor of MAOB, which is the form of MAO selective to dopamine. Thus, it may increase the amount of available dopamine for release. Second, it may protect dopamine neurons by reducing the oxidative stress concomitant with dopamine metabolism (Olanow 1997). Third, L-deprenyl is metabolized into amphetamine and methamphetamine, which may contribute to their antiparkinsonian effects. Unlike other treatments for Parkinson s disease, L-deprenyl seems to slow the progression of the disease. Tolcapone (Tasmar) is a COMT inhibitor, which prevents extracellular breakdown of dopamine. 

COMT) and monoamineoxidase (MAO), is another means to increase actual available dopamine concentration (COMT-inhibitors, p. 188), MAOe-inhibi-tors, p. 88,188). 

Tolcapone (Tasmar) [Antiparkinsonion Agent/COMT Inhibitor]... 

WARNING Cases of fulminant liver failure resulting in death have occurred Uses Adjunct to carbidopa/levodopa in Parkinson Dz Action COMT inhibitor slows levodopa metabolism Dose 100 mg PO tid w/ 1st daily levodopa/carbidopa dose, then dose 6 12 h later -1- w/ renal impair Caution [C, ] Contra Hqjatic impair, w/ nonselective MAOI Disp Tabs SE Constipation, XCTOstomia, vivid dreams, hallucinations, anorexia, N/D, orthostasis, liver failure, Rhabdomyolysis Interactions T Effects OF CNS dqjressants, SSRIs, TCAs, warfarin, EtOH t risk of hypotensive crisis W/ nonselective MAOIs (phenelzine, tranylc5 promine) EMS Has been associated w/ liver failure and death may experience hallucinations concurrent EtOH use can T CNS dqjression T effects of warfarin severe D is common sevoal wks afto starting OD May cause NA and dizziness... 

---