BIA 3-202, a novel catechol- O-methyltransferase inhibitor, enhances the availability of l-DOPA to the brain and reduces its O-methylation

Abstract

1-[3,4-Dihydroxy-5-nitrophenyl]-2-phenyl-ethanone (BIA 3-202) is a new long-acting catechol- O-methyltransferase (COMT) inhibitor with limited access to the brain. The present study evaluated the interference of BIA 3-202 upon levels of l-3,4-dihydroxyphenylalanine ( l-DOPA) and metabolites in plasma (3- O-methyl- l-DOPA) and brain [3- O-methyl- l-DOPA, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] in rats orally treated with l-DOPA (20 mg/kg) plus benserazide (30 mg/kg). At different time points (1, 3 and 6 h) after the administration of BIA 3-202 (0, 3, 10 and 30 mg/kg) or l-DOPA plus benserazide, rats were sacrificed and the right striatum was quickly dissected out and stored for the assay of l-DOPA, 3- O-methyl- l-DOPA, dopamine and amine metabolites. Levels of l-DOPA, 3- O-methyl- l-DOPA, dopamine, DOPAC and HVA in the striatum in l-DOPA plus benserazide-treated rats were higher than in vehicle-treated rats. However, this increase in striatal l-DOPA, dopamine, DOPAC and HVA was, in a dose- and time-dependent manner, even higher ( P<0.05) in rats given BIA 3-202 (3, 10 and 30 mg/kg). This effect was accompanied by a marked decrease in 3- O-methyl- l-DOPA levels in the striatum of l-DOPA plus benserazide-treated rats. Increases in levels of l-DOPA and decreases in 3- O-methyl- l-DOPA levels in plasma also accompanied the administration of BIA 3-202. BIA 3-202 did not significantly affect levels of DOPAC and HVA in the striatum in vehicle-treated rats. It is concluded that administration of BIA 3-202 enhances the availability of l-DOPA to the brain by reducing its O-methylation in the periphery, which may prove beneficial in parkinsonian patients treated with l-DOPA plus an aromatic amino acid decarboxylase inhibitor.