Benzisothiazolinone as a useful template for the design of new monoacylglycerol lipase inhibitors: investigation of the target residues and comparison with octhilinone.

The regulation of 2-arachidonoylglycerol (2-AG) levels is a major issue as 2-AG has been proven to participate in numerous physiopathological phenomena such as neuroprotection or analgesia. Octhilinone, a cysteine-reagent compound, has recently been shown to inhibit in the nanomolar range monoacylglycerol lipase (MAGL), the major enzyme responsible for the degradation of 2-AG. Here, we further investigate the mechanism by which octhilinone and its benzisothiazolinone analog inhibit human MAGL. We also provide new information on the structural requirements for MAGL inhibition by these compounds. Finally, we describe for N-octylbenzisothiazolinone a mode of inhibition which is partially different from that described for octhilinone, especially with regard to the targeted cysteine residues in the vicinity of the catalytic site.

Dual inhibition of MAGL and type II topoisomerase by N-phenylmaleimides as a potential strategy to reduce neuroblastoma cell growth.

The endocannabinoid system is implicated in numerous physiopathological processes while more and more pieces of evidence wave the link between this complex machinery and cancer related phenomenon. In these lines, we confirmed the effects of 2-arachidonoylglycerol (2-AG), the main endocannabinoid, on neuroblastoma cells proliferation in vitro, and proved that some N-phenylmaleimide compounds that were previously shown as MAGL inhibitors can also inhibit type 2 topoisomerase. We also shed light on their antiproliferative effects on a neuroblastoma cell line. In order to establish a link between MAGL inhibition, topoisomerase inhibition and the effects on N1E-115 cells, we tested combinations of maleimides or known endocannabinoid metabolism inhibitors and 2-AG, the major MAGL substrate, on N1E-115 cells. However, none of the inhibitors tested, except the carbamate CAY10499, managed to increase 2-AG's effects. Even the MAGL reference inhibitor JZL184 failed to induce a stronger inhibition of proliferation.

Synthesis and in vitro evaluation of N-substituted maleimide derivatives as selective monoglyceride lipase inhibitors.

The endocannabinoid 2-arachidonoylglycerol (2-AG) plays a major role in many physiological processes, and its action is quickly terminated via enzymatic hydrolysis catalyzed by monoglyceride lipase (MGL). Regulating its endogenous level could offer therapeutic opportunities; however, few selective MGL inhibitors have been described so far. Here, we describe the synthesis of N-substituted maleimides and their pharmacological evaluation on the recombinant human fatty acid amide hydrolase (FAAH) and on the purified human MGL. A few N-arylmaleimides were previously described ( Saario , S. M. ; Salo , O. M. ; Nevalainen , T. ; Poso , A. ; Laitinen , J. T. ; Jarvinen , T. ; Niemi , R. Characterization of the Sulfhydryl-Sensitive Site in the Enzyme Responsible for Hydrolysis of 2-Arachidonoylglycerol in Rat Cerebellar Membranes . Chem. Biol. 2005 , 12 , 649 - 656 ) as MGL inhibitors, and along these lines, we present a new set of maleimide derivatives that showed low micromolar IC(50) and high selectivity toward MGL vs FAAH. Then, structure-activity relationships have been investigated and, for instance, 1-biphenyl-4-ylmethylmaleimide inhibits MGL with an IC(50) value of 790 nM. Furthermore, rapid dilution experiments reveal that these compounds act as irreversible inhibitors. In conclusion, N-substituted maleimides constitute a promising class of potent and selective MGL inhibitors.