title: 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.
authors: Department of Research and Development, BIAL, 4785 S. Mamede do Coronado, Portugal.
authors: A
authors: A
authors: Parada
authors: A I
authors: AI
authors: Loureiro
authors: M A
authors: MA
authors: Vieira-Coelho
authors: D
authors: D
authors: Hainzl
authors: P
authors: P
authors: Soares-da-Silva
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D008745:Methylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives
chemical_list: D000098:Acetophenones; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid; D014443:Tyrosine; D007980:Levodopa; D004295:Dihydroxyphenylalanine; D002394:Catechol O-Methyltransferase; C433466:nebicapone; C008404:3-methoxytyrosine; D004298:Dopamine; D006719:Homovanillic Acid