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 (8) and (2R)-(-)-oxiran-2-ylmethyl(4-benzylphenyl)acetate (30) stand out as potent inhibitors of human recombinant MAGL (IC(50) (8) = 4.1 mu M; IC(50) (30) = 2.4 mu M), rat brain monoacylglycerol hydrolysis (IC(50) (8) = 1.8 mu M; IC(50) (30) = 0.68 mu M), and rat brain FAAH (IC(50) (8) = 5.1 mu M; IC(50) (30) = 0.29 mu M). Importantly, and in contrast to the other previously described MAGL inhibitors, these compounds behave as reversible inhibitors either of competitive (8) or noncompetitive nature (30). Hence, they could be useful to explore the therapeutic potential of reversible MAGL inhibitors.

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