title: Novel bioactive metabolites of dipyrone (metamizol).
abstract: Dipyrone is a common antipyretic drug and the most popular non-opioid analgesic in many countries. In spite of its long and widespread use, molecular details of its fate in the body are not fully known. We administered dipyrone orally to mice. Two unknown metabolites were found, viz. the arachidonoyl amides of the known major dipyrone metabolites, 4-methylaminoantipyrine (2) and 4-aminoantipyrine (3). They were identified by ESI-LC-MS/MS after extraction from the CNS, and comparison with reference substances prepared synthetically. The arachidonoyl amides were positively tested for cannabis receptor binding (CB(1) and CB(2)) and cyclooxygenase inhibition (COX-1 and COX-2 in tissues and as isolated enzymes), suggesting that the endogenous cannabinoid system may play a role in the effects of dipyrone against pain.
authors.affiliation: Zentrum für Kinder- und Jugendmedizin, Philipps-Universität, Marburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Rogosch
authors.forename: Christian
authors.initials: C
authors.lastname: Sinning
authors.forename: Agnes
authors.initials: A
authors.lastname: Podlewski
authors.forename: Bernhard
authors.initials: B
authors.lastname: Watzer
authors.forename: Joel
authors.initials: J
authors.lastname: Schlosburg
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.forename: Maria G
authors.initials: MG
authors.lastname: Cascio
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bisogno
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Rolf
authors.initials: R
authors.lastname: Nüsing
authors.forename: Peter
authors.initials: P
authors.lastname: Imming
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000737:chemistry; D000675:Ampyrone / Q000737:chemistry; D000818:Animals; D002490:Central Nervous System / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000592:standards; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004177:Dipyrone / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D012015:Reference Standards; D021241:Spectrometry, Mass, Electrospray Ionization / Q000592:standards
chemical_list: D000631:Aminopyridines; D016861:Cyclooxygenase Inhibitors; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000675:Ampyrone; C061053:4-methylaminopyridine; D004177:Dipyrone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2