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

1-[3,4-Dihydroxy-5-nitrophenyl]-2-phenyl (BIA 3-202) is a new long-acting c atechol-O-methyltransferase (COMT) inhibitor with Limited access to the bra in. The present study evaluated the interference of BIA 3-202 upon levels o f L-3,4-dihydroxyphenylalanine (L-DOPA) and metabolites in plasma (3-O-meth yl-L-DOPA) and brain [3-O-methyl-L-DOPA, dopamine, 3,4-dihydroxyphenylaceti c acid (DOPAC) and homovanillic acid (HVA)] in rats orally treated with L-D OPA (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 qui ckly dissected out and stored for the assay of L-DOPA, 3-O-methyl-L-DOPA, d opamine and amine metabolites. Levels of L-DOPA, 3-O-methyl-L-DOPA, dopamin e, DOPAC and HVA in the striatum in L-DOPA plus benserazide-treated rats we re 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 e ffect was accompanied by a marked decrease in 3-O-methyl-L-DOPA levels in t he 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 accompanie d the administration of BIA 3-202. BIA 3-202 did not significantly affect l evels of DOPAC and HVA in the striatum in vehicle-treated rats. It is concl uded 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 prov e beneficial in parkinsonian patients treated with L-DOPA plus an aromatic amino acid decarboxylase inhibitor. (C) 2001 Elsevier Science B.V. All righ ts reserved.