Inhibition of rat liver and duodenum soluble catechol-O-methyltransferase by a tight-binding inhibitor OR-462

Schultz, Eija; Nissinen, Erkki

doi:10.1016/0006-2952(89)90673-4

Cited by 69 publications

(58 citation statements)

References 11 publications

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“…The results obtained with the recombinant form of rat liver S-COMT showed a Michaelis-Menten behavior for both the catechol (epinephrine) and the methyl donor (SAM) substrates, with kinetic parameters similar to those described in the literature for the native enzyme (Schultz and Nissinen, 1989;Borges et al, 1997;Vieira-Coelho and Soares-da-Silva, 1999). It is also shown that BIA 3-335 is a potent and reversible COMT inhibitor.…”

Section: Discussionsupporting

confidence: 68%

“…BIA 3-335 displayed a competitive type of inhibition to the substrate binding site and an uncompetitive type of inhibition to the SAM binding site with a K i value of 6.0 Ϯ 1.6 nM. It has also been shown that other nitrocatechol derivatives endowed with marked inhibitory activity against COMT, such as tolcapone, [2-(3,4-dihydroxy-2-nitrophenyl-)vinyl]phenylketone, and entacapone display the same type of inhibition mechanism (Schultz and Nissinen, 1989;Perez et al, 1994;Borges et al, 1997;Vieira-Coelho and Soaresda-Silva, 1999). This is probably related to the fact that the SAM binding site is deep in the COMT structure, whereas the substrate binding site is located on the surface of the enzyme and is easily accessible.…”

Section: Discussionmentioning

confidence: 98%

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Kinetics and Crystal Structure of Catechol-O-Methyltransferase Complex with Co-Substrate and a Novel Inhibitor with Potential Therapeutic Application

et al. 2002

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Catechol-O-methyltransferase (COMT; E.C. 2.1.1.6) is a ubiquitous enzyme in nature that plays an important role in the metabolism of catechol neurotransmitters and xenobiotics. In particular, inactivation of drugs such as L-3,4-dihydroxyphenylalanine (L-DOPA) via O-methylation is of relevant pharmacological importance, because L-DOPA is currently the most effective drug used in the treatment of Parkinson's disease. This justified the interest in developing COMT inhibitors as potential adjuncts to L-DOPA therapy. The kinetics of inhibition by BIA 3-335 (1-[3,4-dihydroxy-5-nitrophenyl]-3-(N-3Ј-trifluormethylphenyl)-piperazine-1-propanone dihydrochloride) were characterized using recombinant rat soluble COMT. BIA 3-335 was found to act as a potent, reversible, tight-binding inhibitor of COMT with a K i of 6.0 Ϯ 1.6 nM and displaying a competitive inhibition toward the substrate binding site and uncompetitive inhibition toward the S-adenosyl-L-methionine (SAM) binding site. The 2.0-Å resolution crystal structure of COMT in complex with its cosubstrate SAM and a novel inhibitor BIA 3-335 shows the atomic interactions between the important residues at the active site and the inhibitor. This is the first report of a threedimensional structure determination of COMT complexed with a potent, reversible, and tight-binding inhibitor that is expected to have therapeutic applications.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 98%

Kinetics and Crystal Structure of Catechol-O-Methyltransferase Complex with Co-Substrate and a Novel Inhibitor with Potential Therapeutic Application

et al. 2002

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“…On the other hand, some researchers suggest that CA and DHCA methylation into FA and DHFA respectively may occur in the gut (Booth et al 1957;Chesson et al 1999;Ranganathan & Ramasarma, 1974). In both rats and human subjects, dietary plant phenolics can undergo metabolism to form reactive intermediates by catechol-o-methyltransferases present in the liver, also in the kidneys and gastrointestinal tracts both stomach and intestine (Nissinen et al 1988;Schultz & Nissinen, 1989;Mannisto et al 1992). The lack of circulating levels of luteolin and apigenin could be due to their low concentrations in the test meal administered.…”

Section: Discussionmentioning

confidence: 99%

Absorption and metabolism of bioactive molecules after oral consumption of cooked edible heads ofCynara scolymusL. (cultivar Violetto di Provenza) in human subjects: a pilot study

et al. 2007

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The current growing interest for natural antioxidants has led to a renewed scientific attention for artichoke, due not only to its nutritional value, but, overall, to its polyphenolic content, showing strong antioxidant properties. The major constituents of artichoke extracts are hydroxycinnamic acids such as chlorogenic acid, dicaffeoylquinic acids caffeic acid and ferulic acid, and flavonoids such as luteolin and apigenin glycosides. In vitro studies, using cultured rat hepatocytes, have shown its hepatoprotective functions and in vivo studies have shown the inhibition of cholesterol biosynthesis in human subjects. Several studies have shown the effect on animal models of artichoke extracts, while information on human bioavailability and metabolism of hydroxycinnamates derivatives is still lacking. Results showed a plasma maximum concentration of 6·4 (SD 1.8) ng/ml for chlorogenic acid after 1 h and its disappearance within 2 h (P, 0·05). Peak plasma concentrations of 19·5 (SD6·9) ng/ml for total caffeic acid were reached within 1 h, while ferulic acid plasma concentrations showed a biphasic profile with 6·4 (SD1·5) ng/ml and 8·4 (SD4·6) ng/ml within 1 h and after 8 h respectively. We observed a significant increase of dihydrocaffeic acid and dihydroferulic acid total levels after 8 h (P,0·05). No circulating plasma levels of luteolin and apigenin were present. Our study confirms the bioavailability of metabolites of hydroxycinnamic acids after ingestion of cooked edible Cynara scolymus L. (cultivar Violetto di Provenza).

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“…There have been several separate studies assessing the in vitro potency of entacapone or tolcapone and inhibition kinetics of COMT (Schultz and Nissinen, 1989;Zü rcher et al, 1990b;Nissinen et al, 1992;Borges et al, 1997;VieiraCoelho and Soares-Da-Silva, 1999), but only three groups have compared entacapone and tolcapone under equal experimental conditions. According to Learmonth et al (2002) tolcapone is more potent than entacapone both against rat brain and against liver COMT.…”

Section: Discussionmentioning

confidence: 99%

“…Nitrocatechol-structured COMT inhibitors have been shown to be tight binding inhibitors (Schultz and Nissinen, 1989;Lotta et al, 1995;Borges et al, 1997) that bind to the enzyme with such a high affinity that the amount of free inhibitor molecules is significantly depleted by the formation of the enzyme-inhibitor complex (Copeland, 2000). The IC 50 value observed for tight binding inhibitors varies with total enzyme concentration at a fixed substrate concentration; i.e., the higher the enzyme concentration, the higher the observed IC 50 value.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Entacapone and Tolcapone after Acute and Repeated Administration: A Comparative Study in the Rat

Forsberg

Lehtonen²,

Heikkinen³

et al. 2003

J Pharmacol Exp Ther

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Two catechol-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone, were compared in the rat to elucidate the actual differences between their pharmacokinetics and pharmacodynamics after single and repeated administration. Their inhibitory potencies were also compared in vitro. After intravenous administration (3 mg/kg), the elimination half-life (t 1/2␤ ) of entacapone (0.8 h) was clearly shorter than that of tolcapone (2.9 h). The striatum/serum ratio of tolcapone was 3-fold higher than that of entacapone. After a single oral dose (10 mg/kg), both entacapone and tolcapone produced an equal maximal degree of COMT inhibition in peripheral tissues, but tolcapone inhibited striatal COMT more effectively than did entacapone. After the 7-day treatment (10 mg/kg twice daily), COMT activity had recovered to a level of 67 to 101% of control within 8 h after the last dose of entacapone. In tolcapone-treated animals, there was still extensive COMT inhibition present in peripheral tissues, and the degree of inhibition was higher than that attained after a single dose. The pharmacokinetic-pharmacodynamic modeling revealed that a plateau of COMT inhibition near the maximal attainable inhibition was reached already by plasma concentrations below 2000 ng/ml, both with entacapone and tolcapone. Entacapone and tolcapone inhibited equally rat liver COMT in vitro with K i values of 10.7 and 10.0 nM, respectively. In conclusion, tolcapone has a longer duration of action and a better brain penetration than entacapone. The results also suggest that peripheral COMT is inhibited continuously when tolcapone is dosed at 12-h intervals, but this was not seen with entacapone.The second-generation catechol-O-methyltransferase (COMT, EC 2.1.1.6) inhibitors, entacapone and tolcapone, are indicated as adjuncts to standard levodopa-dopa decarboxylase inhibitor therapy in Parkinson's disease. They increase the bioavailability of levodopa by inhibiting its peripheral metabolism to an inactive metabolite, 3-O-methyldopa. COMT inhibitors improve the efficacy of the levodopa-dopa decarboxylase inhibitor therapy by prolonging the duration of action and the clinical benefit of levodopa (Mä nnistö and Kaakkola, 1999;Kaakkola, 2000).Entacapone and tolcapone apparently behave differently both in experimental animals and humans. However, as a rule, entacapone and tolcapone have been studied only individually; their pharmacokinetics and pharmacodynamics have not been compared thoroughly after single and repeated dosing. Actually, very little is known about their pharmacodynamics in different tissues after repeated dosing. Furthermore, only the relationship between the plasma drug concentration and COMT activity in erythrocytes has been studied previously (Dingemanse et al., 1995(Dingemanse et al., , 1996Forsberg et al., 2002).A few available studies on entacapone and tolcapone in rats suggest that entacapone is eliminated faster than tolcapone and its oral bioavailability is lower than that of tolcapone. After intravenous administration ...

show abstract

Inhibition of rat liver and duodenum soluble catechol-O-methyltransferase by a tight-binding inhibitor OR-462

Cited by 69 publications

References 11 publications

Kinetics and Crystal Structure of Catechol-O-Methyltransferase Complex with Co-Substrate and a Novel Inhibitor with Potential Therapeutic Application

Kinetics and Crystal Structure of Catechol-O-Methyltransferase Complex with Co-Substrate and a Novel Inhibitor with Potential Therapeutic Application

Absorption and metabolism of bioactive molecules after oral consumption of cooked edible heads ofCynara scolymusL. (cultivar Violetto di Provenza) in human subjects: a pilot study

Pharmacokinetics and Pharmacodynamics of Entacapone and Tolcapone after Acute and Repeated Administration: A Comparative Study in the Rat

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