COMT,

Dopamine. Dopamine (DA) (2) is an intermediate in the synthesis of NE and Epi from tyrosine. DA is localized to the basal ganglia of the brain and is involved in the regulation of motor activity and pituitary hormone release. The actions of DA are terminated by conversion to dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase-A and -B (MAO-A and -B) in the neuron following reuptake, or conversion to homovanillic acid (HVA) through the sequential actions of catechol-0-methyl transferase (COMT) and MAO-A and -B in the synaptic cleft. 

Clenbuterol [37148-27-9] C 2H gCl2N20, (6) (54), a nonphenolic analogue of terbutaline, is not susceptible to COMT or to conjugation. It has a long plasma half-life (20 h), but does not seem to differ ia pharmacological half-life from albuterol (55). 

Two important pathways for catecholamine metaboHsm are 0-methylation by COMT, which is cytoplasmicaHy localized, and oxidative deamination by the mitochondrial localized enzyme MAO. There are large amounts of MAO in tissues such as the fiver and the heart which are responsible for the removal of most of the circulating monoamine, including some taken in from the diet. Tyramine is found in high concentrations in certain foods such as cheese, and in wine. Normally, this tyramine is deaminated in the fiver. However, if MAO is inhibited, the tyramine may then be converted into octopamine [104-14-37] which may indirecdy cause release of NE from nerve terminals to cause hypertensive crisis. Thus MAO, which is relatively nonspecific, plays an important role in the detoxification of pharmacologically active amines ingested from the diet. 

Pelletret R. COMTS V3.0 A new simulation environment for multizone airflow modeling. Room Vent 96 conference, Tokyo, May 1996. 

Allard E, et al. Fundamentals of multizone airflow model- COMtS. Coventry Air Infiltration and Ventilation Centre (AI C), 1990. 

Recently the Ar /He — Ne lasers have been employed for the analysis of thin-layei chromatograms [259 — 261]. However, instruments of this type have not yet comt into general use. 

Catechol O-methyltransferase (COMT) is a widespread enzyme that catalyzes the transfer of the methyl group of S-adenosyl-l-methionine (AdoMet) to one of the phenolic group of the catechol substrate (Fig. 1). High COMT activity is found in the liver, kidney and gut wall... 

Catechol-O-Methyltransferase. Figure. 1 The basic function of COMT. Enzymatic O-methylation of the catechol substrate to 3-methoxy (major route) or 4-methoxy (minor route) products in the presence of Mg2+ and S-adenosyl-methionine (AdoMet). 

COMT O-methylates catecholamines and other compounds having a catechol structure including catecholoestrogens (Fig. 2). The two isoforms of... 

Catechol-O-Methyltransferase. Figure 2 Some substrates of COMT. 

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. 

Clinical studies, available only for entacapone and tolcapone, support preclinical findings. A dose-dependent (100-800 mg) inhibition of the COMT activity of the erythrocytes can be seen after nitrocatechols. However, effective and sufficient dose levels of both entacapone and tolcapone, given concomitantly with L-dopa and DDC inhibitors to patients with Parkinson s disease, appear to be 100-200 mg. However, the treatment strategies of entacapone and tolcapone differ entacapone is a short-acting compound that is given with each dose of L-dopa, and COMT activity may even... 

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... 

MAO converts dopamine to DOPAC (3,4-dihydrox-yphenylacetic acid), which can be further metabolized by COMT to form homovanillic acid (HVA). HVA is the main product of dopamine metabolism and the principal dopamine metabolite in urine. Increased neuronal dopaminergic activity is associated with increases in plasma concentrations of DOPAC and HVA. COMT preferentially methylates dopamine at the 3 -hydroxyl position and utilizes S-adenosyl-L-methio-nine as a methyl group donor. COMT is expressed widely in the periphery and in glial cells. In PD, COMT has been targeted since it can convert l-DOPA to inactive 3-OMD (3-O-methyl-dopa). In the presence of an AADC inhibitor such as carbidopa, 3-OMD is the major metabolite of l-DOPA treatment. 

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. 

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