nitecapone and 3-methoxytyrosine

We studied the effectiveness of OR-611 and OR-462, two novel inhibitors of the enzyme catechol-O-methyltransferase (COMT), on 3-O-methyldopa (OMD) formation in cynomolgus monkeys following intravenous levodopa administration. OR-611 dose-dependently reduced the area under the OMD concentration-vs-time curve, reduced maximum plasma OMD concentrations, delayed the time to peak OMD levels, reduced systemic levodopa clearance, and prolonged the elimination half-life of levodopa. Similar effects on peripheral levodopa metabolism were seen with doses of 15 mg/kg of OR-611 and OR-462, its sister compound, which lacks the ability to penetrate the central nervous system (CNS).

Topics: Animals; Catechol O-Methyltransferase Inhibitors; Catechols; Levodopa; Macaca fascicularis; Male; Nitriles; Parkinson Disease; Pentanones; Tyrosine

3-O-Methyldopa (OMD) is the principal circulating metabolite formed from exogenously administered levodopa. We studied the effect of nitecapone (OR-462), a novel inhibitor of catechol-O-methyltransferase (COMT), on OMD formation in cynomolgus monkeys following intravenous levodopa administration. The drug does not cross the blood-brain barrier, and therefore inhibits only peripheral OMD formation. At a dose of 5 mg/kg, nitecapone reduced the area under the OMD concentration-time curve by 50%. Inhibition of OMD production was maximal at 65% following a dose of 10 mg/kg. A dose of 15 mg/kg produced no further inhibition. The plasma pharmacokinetics of carbidopa, levodopa, and OMD in the monkeys were similar to those in humans. No adverse physiological effects of nitecapone were observed. In single-dose studies, OR-462 is an effective peripheral COMT inhibitor.

Topics: Animals; Carbidopa; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Levodopa; Macaca fascicularis; Male; Pentanones; Tyrosine

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.

Topics: Animals; Brain; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Drug Interactions; Duodenum; Erythrocytes; In Vitro Techniques; Ketones; Levodopa; Liver; Male; Pentanones; Rats; Rats, Inbred Strains; Tyrosine