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.