Inhibition of catechol-O-methyltransferase activity by two novel disubstituted catechols in the rat

Catechol-O-methyltransferase (COMT) has an important role in the extraneuronal inactivation of catecholamine neurotransmitters and drugs with a catechol structure. Two novel COMT inhibitors, OR-462 and OR-486, were highly effective (IC50 = 18 and 12 nM, respectively) and selective in inhibiting COMT...

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Veröffentlicht in:European journal of pharmacology Jg. 153; H. 2-3; S. 263
Hauptverfasser: Nissinen, E, Lindén, I B, Schultz, E, Kaakkola, S, Männistö, P T, Pohto, P
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Netherlands 24.08.1988
Schlagworte:
Animals
Brain - enzymology
Carbidopa - administration & dosage
Carbidopa - pharmacology
Catechol O-Methyltransferase Inhibitors
Catechols - administration & dosage
Catechols - pharmacology
Drug Interactions
Duodenum - enzymology
Erythrocytes - enzymology
In Vitro Techniques
Ketones - pharmacology
Levodopa - administration & dosage
Levodopa - blood
Levodopa - pharmacology
Liver - enzymology
Male
Pentanones - administration & dosage
Pentanones - pharmacology
Rats
Rats, Inbred Strains
Tyrosine - analogs & derivatives
Tyrosine - blood
ISSN:0014-2999
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Zusammenfassung:Catechol-O-methyltransferase (COMT) has an important role in the extraneuronal inactivation of catecholamine neurotransmitters and drugs with a catechol structure. Two novel COMT inhibitors, OR-462 and OR-486, were highly effective (IC50 = 18 and 12 nM, respectively) and selective in inhibiting COMT activity in vitro. Tyrosine hydroxylase was not inhibited until micromolar concentrations of these compounds were used: the IC50 values for OR-462 and OR-486 were 10 and 14 microM, respectively. The IC50 values for dopamine-beta-hydroxylase, dopa-decarboxylase and monoamine oxidase forms A and B were greater than 50 microM. In studies ex vivo oral OR-462 inhibited mainly the COMT activity in the duodenum while OR-486 inhibited COMT activity in the liver and red blood cells as well. Oral OR-462 did not penetrate into the brain in doses up to 30 mg/kg while the same dose of OR-486 had some effect on striatal COMT activity. When tested in combination with levodopa-carbidopa, orally administered OR-462 and OR-486 were more effective in reducing the formation of 3-O-methyldopa from levodopa than was the levodopa-carbidopa treatment alone. These results indicate that OR-462 and OR-486 are effective and long-lasting inhibitors of COMT activity.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0014-2999
DOI:10.1016/0014-2999(88)90614-0