Structure–Activity Relationship of a New Series of Reversible Dual Monoacylglycerol Lipase/Fatty Acid Amide Hydrolase Inhibitors

The two endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), play independent and nonredundant roles in the body. This makes the development of both selective and dual inhibitors of their inactivation an important priority. In this work we report a new series of inhibitors of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Among them, (±)-oxiran-2-ylmethyl 6-(1,1′-biphenyl-4-yl)­hexanoate (<b>8</b>) and (2<i>R</i>)-(−)-oxiran-2-ylmethyl­(4-benzylphenyl)­acetate (<b>30</b>) stand out as potent inhibitors of human recombinant MAGL (IC₅₀ (<b>8</b>) = 4.1 μM; IC₅₀ (<b>30</b>) = 2.4 μM), rat brain monoacylglycerol hydrolysis (IC₅₀ (<b>8</b>) = 1.8 μM; IC₅₀ (<b>30</b>) = 0.68 μM), and rat brain FAAH (IC₅₀ (<b>8</b>) = 5.1 μM; IC₅₀ (<b>30</b>) = 0.29 μM). Importantly, and in contrast to the other previously described MAGL inhibitors, these compounds behave as reversible inhibitors either of competitive (<b>8</b>) or noncompetitive nature (<b>30</b>). Hence, they could be useful to explore the therapeutic potential of reversible MAGL inhibitors