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Entacapone, OR-611, was found to be a potent peripherally acting inhibitor of catechol-O-methyltransferase (COMT). IC50 values of 10 nmol/l and 160 nmol/l 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 Ki-value of 14 nmol/l 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-O-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 3OMD 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.

A series of disubstituted catechol derivatives was synthesized and tested as potential COMT inhibitors. The most active compounds were more than 1000 times more potent (IC50 = 3-6 nM) in vitro than the known COMT inhibitor, 3',4'-dihydroxy-2-methylpropiophenone (U 0521, IC50 = 6000 nM). The new compounds were also highly selective COMT inhibitors with no activity against other essential enzymes involved in the synthesis and metabolism of catecholamines.

A deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase(HGPRT) is associated with a varying clinical picture which may include hyperuricaemia, neurological abnormalities and bizarre self-mutilating behaviour. Due to technical problems with the usual in vitro enzyme assays, it has not been possible to establish a correlation between the degree of the enzyme deficiency and the severity of the clinical manifestations. In this study, the HGPRT activity of 12 patients with various clinical features was measured by quantitative analysis of the incorporation of radioactive precursors into purine compounds in intact fibroblasts. The results demonstrate that a correlation between the severity of the clinical symptoms and the degree of the enzyme deficiency as measured in intact fibroblasts does in fact exist.