Pentti Pohto

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

SummaryEntacapone, OR-611, was found to be a potent peripherally acting inhibitor of catechol-O-methyl-transferase (COMT). IC50 values of 10 nmol/1 and 160 nmol/1 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 K; value of 14 nmol/1 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 3-0-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 30MD 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.

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 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.

Properties of novel effective and highly selective inhibitors of catechol-O-methyltransferase

Novel bisubstituted catechols were found to be potent and highly selective COMT inhibitors in vitro. One of them, OR-462 (3-(3,4-dihydroxy-5-benzylidene)-2,4-pentanedione), was studied also in vivo. When administered to rats orally together with levodopa and carbidopa, OR-462 greatly improved the bioavailability of levodopa and effectively reduced the formation of 3OMD. The levels of levodopa and dopamine were increased also in the striatum, and the 3OMD levels were decreased. The metabolic profile of dopamine demonstrated that COMT inhibition occurred in the peripheral tissues but not in the striatum. OR-462 thus resembled the peripheral inhibitors of dopadecarboxylase. These potent, selective and orally active COMT inhibitors offer a new tool for interfering in the metabolism of various COMT substrates.

Biochemical Properties of OR-1259 - A Positive Inotropic and Vasodilatory Compound with an Antiarrhythmic Effect

OR-1259 is a positive inotropic and vasodilatory compound with antiarrhythmic properties. Biochemically, OR-1259 can act as a troponin modifier, as an phosphodiesterase III inhibitor and as an inhibitor of voltage-sensitive Ca2+ current.