Derivate nichtsteroidaler Antirheumatika als potentielle Cannabinoid- und Vanilloid-Rezeptor Liganden und Fettsäure-Derivate des Metamizols als dessen pharmakologisch aktives Prinzip

This PhD-Thesis deals on the one hand with the potential intervention of metabolites of the nonsteroidal antiinflammatory drugs that are structurally related to the endocannabinoids and endovanilloids into the endogenous cannabinoid and vanilloid system. On the other hand the molecular mechanism of action of dipyrone (=metamizol) was examined and could be clarified at least partly. In the first part dopamids, vanillylamids und 2-glycerolesters of Diclofenac, Ibuprofen, Indometacin, Naproxen and Flurbiprofen were synthesized. It could be shown, that the dopamids and vanillylamids of Diclofenac and Indometacin trigger by TRPV1 receptor activation calcium influx into HEK 293 cells that were transfected with hVR1 cDNA (EC50 between 0.26 and 1.50 µM). Since the vanillylamids cannot arise in vivo because of the lack of vanillylamin they are “just” suitable as pharmacological tools or as templates for new TRPV1-Agonisten. The dopamids could arise theoretically in vivo; but till now, anyone has searched for them yet. Both the ethanolamids produced in the context of my master thesis and dopamids, vanillylamids and 2-glycerolesters of Ibuprofen, Naproxen und Flurbiprofen were no ligands at CB- and TRPV1-receptors. Also an inhibition of FAAH could not be proved. Thereby our hypothesis that NSARs which are similar to the endocannabinoids achieve their effect partly about this metabolite was not confirmed. The second part deals with the clearing up of the mechanism of dipyrone. Dipyrone is an analgetic and antipyretic drug. It is hydrolyzed in the stomach rapidly to N-methyl-aminophenazone (MAP) and absorbed as such. Afterwards it gets biotransformed into aminophenazone (AP) and other less important metabolites such as N acetyl-aminophenazone (AAP) and N-formyl-aminophenazone (FAP). However its pharmacological mechanism is still unrevealed. We have designed and synthesized arachidonic acid derivatives of N methyl-aminophenazone (AA-MAP) and aminophenazone (AA-AP). These metabolites could be found in brain and medulla extracts of mice and rats that have been fed with dipyrone. The arachidonic acid derivative of MAP inhibits COX-1 and COX-2 at low micromolare concentrations. At CB1- and CB2-receptors both arachidonic acid derivatives showed an affinity with a Ki value in the micro-molecular range. Furthermore the emergence of these metabolites could be clarified. In FAAH knockout mice, which were fed with dipyrone, these metabolites could not be found or only in traces, while they were found in wildtyp mice in significant concentration. This points to a key role of FAAH in the emergence of these metabolites.