Discovery of Aryl Formyl Piperidine Derivatives as Potent, Reversible, and Selective Monoacylglycerol Lipase Inhibitors

Most
of the current monoacylglycerol lipase (MAGL) inhibitors function
by an irreversible mechanism of action, causing a series of side effects.
Herein, starting from irreversible inhibitors, 25 compounds were synthesized
and evaluated in vitro for MAGL inhibition, among
which, compound 36 showed the most potent inhibitory
activity (IC50 = 15 nM). Crucially, docking studies demonstrated
that the m-chlorine-substituted aniline fragment
occupied a hydrophobic subpocket enclosed by side chains of Val191,
Tyr194, Val270, and Lys273, which creatively identify a new key anchoring
point for the development of new MAGL inhibitors. Furthermore, in vivo evaluation innovatively revealed that this reversible
inhibitor 36 significantly ameliorated depressive-like
behaviors induced by reserpine. To the best of our knowledge, this
is the first time that reversible inhibitors of MAGL were developed
to support MAGL as a potential therapeutic target for depression.