title: Catechol-O-methyltransferase inhibition in erythrocytes and liver by BIA 3-202 (1-[3,4-dibydroxy-5-nitrophenyl]-2-phenyl-ethanone).
abstract: The present study evaluated the relationship between the degree of catechol-O-methyltransferase (COMT) inhibition in erythrocytes and liver by BIA 3-202 (1-[3,4-dihydroxy-5-nitrophenyl]-2-phenyl-ethanone) and determined its effects upon the O-methylation of L-DOPA in rats orally treated with L-DOPA plus benserazide. The soluble form of COMT (S-COMT) in erythrocytes was endowed with the same affinity as liver S-COMT for the substrate adrenaline. BIA 3-202 inhibited erythrocytes and liver S-COMT with ED50's of 1.9 (0.7, 3.1) and 1.9 (0.5, 3.2) (95% confidence limits) mg kg(-1), respectively. BIA 3-202 reduced the L-DOPA-induced rise of 3-O-methyl-L-DOPA in the peripheral circulation, striatal dialysate levels and striatum, and increased dopamine striatal levels. In BIA 3-202-treated rats the increase in L-DOPA in peripheral blood and striatal dialysates was significantly greater than in vehicle-treated rats. It is concluded that S-COMT activity in erythrocytes may provide important information on the pharmacodynamic profile of COMT inhibitors. The novel COMT inhibitor BIA 3-202 is a potent COMT inhibitor that enhances the availability of L-DOPA to the brain by reducing its O-methylation, which may prove beneficial in patients with Parkinson's disease treated with L-DOPA.
authors.affiliation: Department of Research & Development, BIAL, S. Mamede do Coronado, Portugal. psoares.silva@bial.com
authors.forename: Patrício
authors.initials: P
authors.lastname: Soares-da-Silva
authors.forename: Maria A
authors.initials: MA
authors.lastname: Vieira-Coelho
authors.forename: António
authors.initials: A
authors.lastname: Parada
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D001545:Benserazide / Q000494:pharmacology; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004347:Drug Interactions; D004912:Erythrocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D007980:Levodopa / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008745:Methylation; D008750:Methyldopa / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D017551:Microdialysis; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000098:Acetophenones; D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D007980:Levodopa; D008750:Methyldopa; D004295:Dihydroxyphenylalanine; D001545:Benserazide; C021712:3-O-methylmethyldopa; D002394:Catechol O-Methyltransferase; C433466:nebicapone