Synthesis, characterization and pharmacological evaluation of inhibitors of monoacylglycerol lipase (MAGL), the enzyme that hydrolyses 2-arachidonoylglycerol

The use of cannabis has been known for ages but breakthroughs in the knowledge of its components and the complex architecture of what is named nowadays endocannabinoid system have just been made in the last decades. Its main actors, anandamide and 2-arachidonoylglycerol are endogenous lipids known as endocannabinoids that are produced to modulate a series of pathways in the central nervous system as well as in the periphery. However, their action at specific receptors named cannabinoid receptors, are rapidly disrupted since they are respectively hydrolyzed by two major enzymes, the fatty acid amide hydrolase and the monoacylglycerol lipase (MAGL). In order to extend the duration of the pharmacological effects of 2-arachidonoylglycerol, we designed new tools to prevent the hydrolytic action of MAGL. \nIn these lines, we describe three different strategies to achieve our goal: in a first time, starting from the pharmacomodulations of 2-oleoylglycerol, we developed a series of substrate analogues with micromolar activity on MAGL. \nThe second part of the project was the pharmacomodulation of the N-phenylmaleimide scaffold. While few maleimides had been previously shown to inhibit MAGL, we developed a series of compounds and explored the structure-activity relationships of this family. We further characterized their mechanism of action and designed a new lead. We then improved the initial template, using the benzisothiazolinone scaffold as a new guide-structure. We proposed a series of modifications to evaluate this structure and validated the template. Finally, we characterized the mechanism of action on MAGL for two compounds, and unravelled the targeted amino-acids. \nIn the last part of this work, we investigated the pharmacological potential of compounds belonging to the second series of inhibitors, based on the maleimide scaffold. Since the involvement of MAGL in the proliferative processes and the aggressiveness of cancer cells has been demonstrated, we tested some of maleimide derivatives on both topoisomerase and MAGL, as N-methyl and N-ethylmaleimide had been previously shown as type-II topoisomerase inhibitors too.\nExploring both the medicinal chemistry and the pharmacology sides of a med chem project, this thesis presents three families of MAGL inhibitors with different pharmacological profiles (from reversible to irreversible inhibitors) and their potential implication in cancer related phenomena.