title: Pharmacological profile of opicapone, a third-generation nitrocatechol catechol-O-methyl transferase inhibitor, in the rat.
abstract: OBJECTIVE
  Catechol-O-methyltransferase (COMT) is an important target in the levodopa treatment of Parkinson's disease; however, the inhibitors available have problems, and not all patients benefit from their efficacy. Opicapone was developed to overcome those limitations. In this study, opicapone's pharmacological properties were evaluated as well as its potential cytotoxic effects.
  
  
  METHODS
  The pharmacodynamic effects of opicapone were explored by evaluating rat COMT activity and levodopa pharmacokinetics, in the periphery through microdialysis and in whole brain. The potential cytotoxicity risk of opicapone was explored in human hepatocytes by assessing cellular ATP content and mitochondrial membrane potential.
  
  
  RESULTS
  Opicapone inhibited rat peripheral COMT with ED50 values below 1.4 mg⋅kg(-1) up to 6 h post-administration. The effect was sustained over the first 8 h and by 24 h COMT had not returned to control values. A single administration of opicapone resulted in increased and sustained plasma levodopa levels with a concomitant reduction in 3-O-methyldopa from 2 h up to 24 h post-administration, while tolcapone produced significant effects only at 2 h post-administration. The effects of opicapone on brain catecholamines after levodopa administration were sustained up to 24 h post-administration. Opicapone was also the least potent compound in decreasing both the mitochondrial membrane potential and the ATP content in human primary hepatocytes after a 24 h incubation period.
  
  
  CONCLUSIONS
  Opicapone has a prolonged inhibitory effect on peripheral COMT, which extends the bioavailability of levodopa, without inducing toxicity. Thus, it exhibits some improved properties compared to the currently available COMT inhibitors.
authors.affiliation: Department of Research and Development, BIAL - Portela & Cª, S.A., São Mamede do Coronado, Portugal.
authors.forename: M J
authors.initials: MJ
authors.lastname: Bonifácio
authors.forename: L
authors.initials: L
authors.lastname: Torrão
authors.forename: A I
authors.initials: AI
authors.lastname: Loureiro
authors.forename: P N
authors.initials: PN
authors.lastname: Palma
authors.forename: L C
authors.initials: LC
authors.lastname: Wright
authors.forename: P
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001577:Benzophenones / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors / Q000494:pharmacology*; D002396:Catechols / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007980:Levodopa / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008954:Models, Biological; D009570:Nitriles / Q000494:pharmacology; D009596:Nitrophenols / Q000494:pharmacology; D010069:Oxadiazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D017208:Rats, Wistar; D000077867:Tolcapone
chemical_list: D000978:Antiparkinson Agents; D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D009570:Nitriles; D009596:Nitrophenols; D010069:Oxadiazoles; D007980:Levodopa; C071192:entacapone; D000255:Adenosine Triphosphate; D000077867:Tolcapone; D002394:Catechol O-Methyltransferase; C549349:opicapone