Discrepancy in Reported and Observed Monoacylglycerol Lipase Inhibition of Aryl Formyl Piperidine Containing Potent and Highly Selective Monoacylglycerol Lipase Inhibitor

Zhi et al. reported compound 36 as a potent reversible inhibitor of human recombinant monoacylglycerol lipase (hrMAGL; IC 50 = 15 nM) with excellent selectivity over other targets. To develop potential PET tracers for imaging MAGL, we synthesized compound 36 as a reference compound. Surprisingly, we observed a significant discrepancy between the reported potency and our findings in two well‐established in vitro assays. Compound 36 exhibited no inhibition of endocannabinoid hydrolysis in HEK293 lysates overexpressing human MAGL in a glycerol‐based assay at 1 μM. In the competitive ABPP assay, it appeared completely inactive inhibiting MAGL in mouse whole‐brain proteome even at 100 μM. In addition, eight structural analogs ( 2 – 9 ) of compound 36 also failed to show any significant MAGL inhibition. Interestingly, when the synthetic substrate 4‐nitrophenyl acetate, also used by Zhi et al., was employed, compound 36 inhibited MAGL more effectively than in glycerol‐based assay, with an IC 50 value of 143 nM, being almost 10‐fold less potent than reported. In our reversibility assay, compound 36 exhibited measurable MAGL inhibition only at a concentration of 100 μM. In summary, this study contradicts the earlier report and therefore, compound 36 should be used with caution as a research tool in studies exploring MAGL inhibition.