title: Inhibition of catechol-O-methyltransferase activity by two novel disubstituted catechols in the rat.
abstract: 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.
authors.affiliation: Orion Pharmaceutica, Research Center, Espoo, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Nissinen
authors.forename: I B
authors.initials: IB
authors.lastname: Lindén
authors.forename: E
authors.initials: E
authors.lastname: Schultz
authors.forename: S
authors.initials: S
authors.lastname: Kaakkola
authors.forename: P T
authors.initials: PT
authors.lastname: Männistö
authors.forename: P
authors.initials: P
authors.lastname: Pohto
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D002230:Carbidopa / Q000008:administration & dosage / Q000494:pharmacology; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D004386:Duodenum / Q000201:enzymology; D004912:Erythrocytes / Q000201:enzymology; D066298:In Vitro Techniques; D007659:Ketones / Q000494:pharmacology*; D007980:Levodopa / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D008297:Male; D010422:Pentanones / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D007659:Ketones; D010422:Pentanones; D014443:Tyrosine; D007980:Levodopa; C057364:nitecapone; D002230:Carbidopa; C008404:3-methoxytyrosine; C057726:OR486