Showing papers on "Catechol-O-methyl transferase published in 1992"

Characteristics of catechol O-methyltransferase (COMT) and properties of selective COMT inhibitors

Abstract: The enzyme-catalyzed O-methylation of catecholamines was first described by Axelrod and coworkers in the late 1950’s [1–3]. They called the responsible enzyme catechol O-methyltransferase (COMT). During the subsequent 15 years the enzyme was partially purified, its distribution was established, several reaction mechanisms were proposed, and a number of inhibitors were described. The results of this study period were extensively reviewed by Guldberg and Marsden in 1975 [4].

Biochemical and pharmacological properties of a peripherally acting catechol-O-methyltransferase inhibitor entacapone

Abstract: Entacapone, OR-611, was found to be a potent peripherally acting inhibitor of catechol-O-methyltransferase (COMT). IC50 values of 10 nmol/l and 160 nmol/l were obtained for rat duodenum and liver-soluble COMT, respectively. There were no effects on other catecholamine metabolizing enzymes. Entacapone showed reversible, tight-binding type of inhibition of soluble rat liver COMT with a Ki-value of 14 nmol/l and it also caused 50% inhibition of rat duodenal, erythrocyte, liver and striatal COMT activity 1 h after oral dosing with 1.1, 5.4, 6.7 and 24.2 mg/kg, respectively. However, penetration of entacapone into the brain was poor, since the formation of homovanillic acid (HVA), the O-methyl metabolite of dopamine in the striatum, was not reduced, even after the highest dose of 30 mg/kg. In rat blood serum, the concentration of 3-O-methyldopa (3OMD), the O-methylated product of L-dopa, was reduced in a dose-dependent manner, and the concentration of L-dopa was increased after the administration of entacapone (3-30 mg/kg p.o.) together with L-dopa + carbidopa. These changes were reflected, in the striatum, by a significant rise in the dopamine concentration and a reduction in the 3OMD concentration. Consequently, when entacapone was added to the treatment with L-dopa + carbidopa, the dose of L-dopa could be lowered from 50 mg/kg to 15 mg/kg in order to produce the same striatal dopamine concentrations as with 50 + 50 mg/kg of L-dopa + carbidopa alone.

Different in vivo properties of three new inhibitors of catechol O-methyltransferase in the rat.

Abstract: 1. We compared three new catechol O-methyltransferase (COMT) inhibitors (OR-611, Ro 40-7592 and CGP 28014; 10 and 30 mg kg-1, i.p.) in male rats given levodopa (L-DOPA, 50 mg kg-1, i.p.) and carbidopa ((-)-L-alpha-methyl dopa, 50 mg kg-1, i.p.). In some studies pretreatment with pargyline (80 mg kg-1, i.p.) was used to block the function of monoamine oxidase (MAO). 2. Decreases of hypothalamic and striatal 3-O-methyl-dopa (3-OMD) levels were used as measures of the inhibition of peripheral COMT. The inhibition of brain COMT activity was estimated by decreases of hypothalamic and striatal homovanillic acid (HVA) and 3-methoxytyramine (3-MT; after pargyline) levels. 3. The three COMT inhibitors studied had different individual characteristics. OR-611 was primarily a peripherally acting COMT inhibitor, decreasing 3-OMD levels in the striatum (to 31-52%) and in the hypothalamus (to 16-27%) both in the control and pargyline-treated animals at 1 and 3 h. It did not have any effect on brain HVA and 3-MT. 3. Ro 40-7592 was a broad spectrum COMT inhibitor decreasing striatal and hypothalamic 3-OMD (always to less than 30%), HVA (to less than 50%) and 3-MT levels (to less than 23%) significantly both at 1 and 3 h. It was more potent than OR-611. 4. CGP 28014 functioned as a weak COMT inhibitor in the periphery inhibiting 3-OMD formation only at 3 h. In contrast, it was fairly potent in decreasing the brain HVA and 3-MT levels at 1 h (to 37-22% and 42-35% in the striatum, and to 57-33% and 64-35% in the hypothalamus, respectively) but not at 3 h. Since CGP 28014, unlike OR-611 and Ro 40-7592, did not generally increase the brain DOPA, dopamine or DOPAC levels, it was not a typical COMT inhibitor.

Extracellular concentrations of dopamine and metabolites in the rat caudate after oral administration of a novel catechol-O-methyltransferase inhibitor Ro 40-7592.

Abstract: The effect of the systemic administration of a novel, orally active, catechol-O-methyltransferase (COMT) inhibitor, Ro 40–7592, on the in vivo extracellular concentrations of dopamine (DA) and its metabolites, dihydroxy-phenylacetic acid (DOPAC) and homovanillic acid (HVA), was studied by transcerebral microdialysis in the dorsal caudate of freely moving rats. Ro 40–7592 (at doses of 3.0, 7.5, and 30 mg/kg p.o.) elicited a marked and long-lasting reduction of HVA, and at doses of 7.5 and 30 mg/kg, an increase of DOPAC output, but it failed to increase DA output. The administration of L-β-3,4-dihydroxyphenylalanine (L-DOPA, 20 and 50 mg/kg p.o.) with a DOPA decarboxylase inhibitor (benserazide) increased both HVA and DOPAC output, but failed to modify significantly extracellular DA concentrations in dialysates; in contrast, combined administration of L-DOPA + benserazide with Ro 40–7592 (30 mg/ kg p.o.) resulted in a significant increase in DA output. Ro 40–7592 prevented the L-DOPA-induced increase in HVA output and markedly potentiated the increase in DOPAC output. To investigate to what extent the increase in extra cellular DA concentrations was related to an exocitotic release, tetrodotoxin (TTX) sensitivity was tested. Addition of TTX to Ringer, although abolishing DA output in the absence of L-DOPA, partially reduced it in the presence of L-DOPA + Ro 40–7592 and even more so after L-DOPA without the COMT inhibitor. The results of the present study suggest that metabolism through COMT regulates extracellular concentrations of DA formed from exogenously administered L-DOPA but not of endogenous DA. Therefore, inhibition of COMT results in a potentiation of L-DOPA effects not only by inhibition of its peripheral metabolism (conversion to 3-methoxy-DOPA), but also by inhibition of the metabolism of its active metabolite, DA, in the brain.

Catechol‐O‐methyltransferase inhibition increases striatal L‐dopa and dopamine: An in vivo study in rats

Abstract: We administered Ro 40–7592, an inhibitor of the enzyme catechol-O-methyltransferase (COMT) that crosses the blood-brain barrier, to rats and monitored extracellular catecholamine levels in the corpus striatum before and after the intraperitoneal administration of a bolus of 1-dopa Acute administration of Ro 40–7592 increased basal levels of 1-dopa and dihydroxyphenylacetic acid (DOPAC) and decreased basal homovanillic acid (HVA) levels, but did not affect basal dopamine levels In rats treated with Ro 40–7592, 1-dopa administration produced a greater increase in striatal levels of 1-dopa, dopamine, and DOPAC than it did in controls, while HVA formation was attenuated We conclude that inhibition of COMT activity promotes central dopamine synthesis and release following administration of pharmacologic doses of 1-dopa

Dopamine and adrenaline, but not isoprenaline, are substrates for uptake and metabolism in isolated perfused lungs of rats.

Abstract: The uptake and subsequent metabolism by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) of dopamine, adrenaline, isoprenaline and noradrenaline in isolated perfused lungs of rats has been examined. In lung preparations in which COMT and MAO were inhibited, the uptake of 3H-labelled dopamine, (−)-adrenaline and (−)-noradrenaline, but not (±)-isoprenaline, was reduced by cocaine (10 or 100 μmol/l) The rank order of the Km values of the amines that were substrates for uptake in the lungs were: dopamine (0.246 μmol/l) < noradrenaline (0.967 μmol/l) < adrenaline (3.32 μmol/l). These results are consistent with transport of catecholamines in rat lungs by Uptake1. In lung preparations with COMT and MAO intact, dopamine and noradrenaline were removed from the circulation (50% and 32%, respectively) and mainly metabolized. There was very little (3.0%) removal of isoprenaline by the lungs and adrenaline was not included in this part of the study. In lung preparations in which only MAO was inhibited, the rank order of COMT activity for O-methylation of the amines was dopamine ≪ noradrenaline ≥ adrenaline (kCOMT values: 4.98 min−1, 0.357 min−1, and 0.234 min−1, respectively). If dopamine or adrenaline are perfused through the pulmonary circulation in isolated lungs of the rat, they are taken up and then metabolized by COMT and MAO, as also occurs for noradrenaline. Isoprenaline is not a substrate for uptake in the lungs. There was less uptake of adrenaline than noradrenaline, indicating that uptake and metabolism in the lungs may not be a significant removal process for adrenaline in the circulation of rats in vivo. The more marked uptake of dopamine (than of noradrenaline) indicates that uptake and metabolism by the lungs, at least in the rat, may play an important role in the removal of dopamine from the circulation in vivo.