title: Acute toxicity of three new selective COMT inhibitors in mice with special emphasis on interactions with drugs increasing catecholaminergic neurotransmission.
abstract: 3-Nitropyrocatechols are very potent and selective inhibitors of catechol-O-methyltransferase (COMT). LD50 values of three of these compounds were assessed after intraperitoneal administration with a special emphasis on interactions with drugs increasing catecholaminergic neurotransmission. LD50 values of the inhibitors varied from 137 mg/kg (Ro 41-0960) to 507 mg/kg (OR-462) and 544 mg/kg (OR-611). The LD50 value of Ro 41-0960 was significantly lower than that of OR-462 and OR-611 (P less than 0.05). At toxic dose levels all inhibitors caused convulsions and hypomotility. OR-462 and OR-611 had statistically significant mortality increasing interaction with 20 mg/kg of nomifensine (P less than 0.05) and the former also with 10 mg/kg of amphetamine (P less than 0.05). Owing to their high therapeutic indexes these compounds can be considered useful new tools in pharmacological research.
authors.affiliation: Department of Pharmacology and Toxicology, University of Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Törnwall
authors.forename: P T
authors.initials: PT
authors.lastname: Männistö
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001577:Benzophenones / Q000633:toxicity; D002230:Carbidopa / Q000494:pharmacology; D065098:Catechol O-Methyltransferase Inhibitors; D002395:Catecholamines / Q000502:physiology*; D002396:Catechols / Q000633:toxicity; D003010:Clorgyline / Q000494:pharmacology; D003292:Convulsants; D003891:Desipramine / Q000494:pharmacology; D004347:Drug Interactions; D007928:Lethal Dose 50; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009570:Nitriles; D009627:Nomifensine / Q000494:pharmacology; D010422:Pentanones / Q000633:toxicity; D012642:Selegiline / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D002395:Catecholamines; D002396:Catechols; D003292:Convulsants; D009570:Nitriles; D010422:Pentanones; C071721:Ro 41-0960; D009627:Nomifensine; D012642:Selegiline; D015016:Yohimbine; D007980:Levodopa; C071192:entacapone; C057364:nitecapone; D000661:Amphetamine; D003010:Clorgyline; D002230:Carbidopa; D003891:Desipramine