Structure–Activity
Relationship of a New Series
of Reversible Dual Monoacylglycerol Lipase/Fatty Acid Amide Hydrolase
Inhibitors
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Abstract
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 (IC<sub>50</sub> (<b>8</b>) = 4.1 μM; IC<sub>50</sub> (<b>30</b>) = 2.4 μM), rat brain monoacylglycerol hydrolysis
(IC<sub>50</sub> (<b>8</b>) = 1.8 μM; IC<sub>50</sub> (<b>30</b>) = 0.68 μM), and rat brain FAAH (IC<sub>50</sub> (<b>8</b>) = 5.1 μM; IC<sub>50</sub> (<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