Showing papers on "Catechol-O-methyl transferase published in 1990"

Effect of a novel catechol-O-methyltransferase inhibitor, nitecapone, on the metabolism of L-dopa in healthy volunteers

Abstract: A new catechol-O-methyltransferase (COMT) inhibitor, nitecapone, was given in increasing doses of 0-100 mg concomitantly with L-Dopa/carbidopa (100/25 mg or 100/100 mg) to healthy male volunteers. Plasma concentrations of L-Dopa, 3-O-methyldopa (3-OMD), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), as well as the excretion of catecholamine metabolites in urine were followed to evaluate the changes in the metabolism of L-Dopa after nitecapone. Plasma concentrations of nitecapone and the soluble COMT activity in erythrocytes were also measured. The area under the plasma concentration-time curves (AUC) values for plasma nitecapone, L-Dopa and its metabolites were calculated. Nitecapone dose-dependently inhibited the soluble COMT activity in erythrocytes at 30 min after drug intake. Nitecapone slightly but significantly increased the relative bioavailability of L-Dopa. The AUC values of plasma 3-OMD decreased dose-dependently after nitecapone, and those of HVA decreased less, whereas the AUC values of DOPAC increased significantly. The elevation of the dose of carbidopa from 25 to 100 mg increased the AUC value of L-Dopa, but the effect of nitecapone was not clearly modified. Nitecapone decreased the excretion of the methylated dopamine metabolites 3-methoxytyramine (3-MT) and HVA at an L-Dopa/carbidopa dose of 100/25 mg. At a dose of 100/100 mg, the excretion of metanephrine, in addition to 3-MT and HVA, was also significantly decreased by nitecapone. The biochemical changes in L-Dopa metabolism and erythrocyte COMT activity indicate that nitecapone is an active COMT inhibitor in humans, when given orally in single doses. The changes in L-Dopa metabolism by COMT inhibitor warrant further clinical studies in Parkinson's disease.

Inhibition of catechol-O-methyltransferase by N-(3,4-dihydroxyphenyl) maleimide.

Abstract: Catechol-O-methyltransferase (COMT) is inhibited rapidly and irreversibly by N-(3,4-dihydroxyphenyl) maleimide. S-adenosylmethionine (AdoMet) and magnesium ions protect the enzyme from inactivation by this compound, but no protection is observed by the catechol substrate. However, the corresponding succinimide analogue shows a reversible inhibition of COMT, which is competitive with pyrocatechol-phthalein and non-competitive with AdoMet. Amino-group reagents also inhibit COMT and this inhibition is protected by AdoMet, suggesting that sulphydryl and amino groups essential for activity are located in an AdoMet-binding site on COMT. The maleimide derivative may be considered to be an active-site directed inhibitor.

Effect of the new selective COMT inhibitor CGP 28014 A on the formation of 3-O-methyldopa (3OMD) in plasma of healthy subjects.

Abstract: CGP 28 014 A is a specific inhibitor of catechol-O-methyl transferase (COMT). The effect on COMT was assessed with the levodopa test in 5 unmedicated subjects and after pretreatment with 200–600 mg CGP 28 014 p.o. Plasma concentrations of DOPA, 3-O-methyldopa (3OD), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid were measured. CGP 28 014 A decreased 3OMD not dose-related by 67% (p < 0.05). This, and an increase of DOPAC shows COMT inhibition by this compound in humans.

L-dopa as Substrate for human duodenal catechol-O-methyltransferase and aromatic L-amino acid decarboxylase

Abstract: Catechol-O-methyltransferase (COMT) and aromatic L-amino acid decarboxylase (AADC) activities were determined in human gastrointestinal samples. L-dopa was used as the substrate and the reaction products 3-O-methyldopa (3OMD) and dopamine were separated by reversed phase HPLC and detected by electrochemical or UV detection. COMT activities varied between 40–350 pmol/mg/min and AADC activities between 100 – 3300 pmol/mg/min in different parts of the gastrointestinal tract. COMT inhibitors nitecapone (OR-462) and OR-611 effectively inhibited human gastrointestinal COMT activity in vitro, the IC50 values ranging from 10–20 nM and 5–75 nM, respectively. In vitro carbidopa inhibited AADC slightly more effectively than benserazide.

Augmentation of the Sterilizing Effect of Neonatal Androgenization with Tropolone, a Catechol-O-Methyltransferase Inhibitor, in Female Rats

Abstract: The influence of tropolone, a catechol-O-methyltransferase (COMT) inhibitor, on the sterilizing effect of neonatal testosterone propionate (TP) has been studied in Wistar female rats. Tropolone-induced changes in COMT activity and noradrenaline (NA) and dopamine (DA) contents in the hypothalamus have been evaluated. Inhibition of COMT activity was maximal 3 h after a single injection of 0.6 mg tropolone on postnatal day 5. An increase in DA level was observed 6 h after drug injection, whereas the NA content was elevated 24 h after tropolone administration. A sexual dimorphism in hypothalamic NA content in rats was found on postnatal day 10: it was higher in males than in females. The rise of catecholamines in the hypothalamus of 10-day-old female rats induced by COMT inhibition with tropolone (0.3 mg on postnatal days 5 and 7) was unable to masculinize developing neuroendocrine regions responsible for sexual cyclicity. At the same time, combined administration of tropolone (0.1 mg daily on postnatal days 4-10) and TP (0.025 mg on day 4) enhanced the sterilizing effect of the androgen. An anovulatory sterility appeared in all experimental animals. It is suggested that a cooperative interaction occurs between catecholamines and sex steroids as determinants of brain sexual differentiation.

Monoclonal antibodies recognizing both soluble and membrane bound catechol-O-methyltransferase.

Abstract: Both cytosolic, soluble and membrane-bound catechol-O-methyltransferase (COMT) from pig and rat liver or kidney were recognized by mouse monoclonal antibodies (MAbs) raised against soluble COMT isolated from pig liver. In ELISA, the MAbs Co 16 and Co 54 reacted better with the pig than with the rat enzyme. The MAb Co 60 showed good reactivity with both pig and rat COMT. In addition, all three MAbs recognize the soluble (23 kDa) as well as the membrane-bound (26 kDa) forms of the COMT enzyme.

The effects of soman in vitro on catechol-O-methyltransferase and monoamine oxidase activities in rabbit tissues.

Abstract: Soman (pinacolyl methylphosphonofluoridate) not only increases acetylcholine levels by inhibiting cholinesterases, it also alters the levels of some other neurotransmitters including norepinephrine, dopamine, and serotonin. Soman also causes an alteration in the activities of the enzymes metabolizing norepinephrine when it is administered to animals. Because these alterations may result from indirect effects on the enzymes, the effects of in vitro application of soman on catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) activities in rabbit tissues were investigated. Enzyme activities were determined in rabbit lung, liver, cerebellum, cerebrum, brain stem, mesenteric artery, pulmonary artery, renal artery, central ear artery, thoracic aorta, and diaphragm. MAO and COMT activities were not affected by soman in any tissues tested, except the lung and liver, where the activity of COMT was increased (p less than 0.05). Thus, reported effects of soman in vivo on norepinephrine, dopamine, or serotonin concentrations, and MAO and COMT activities do not seem to result from direct effects on the activities of these amine-metabolizing enzymes.