Development and Pharmacological Characterization of Selective Blockers of 2‑Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain

We
report the discovery of compound 4a, a potent β-lactam-based
monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible
and stereoselective mechanism of action, high membrane permeability,
high brain penetration evaluated using a human in vitro blood–brain
barrier model, high selectivity in binding and affinity-based proteomic
profiling assays, and low in vitro toxicity. Mode-of-action studies
demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol
and behaves as a cannabinoid (CB1/CB2) receptor indirect agonist.
Administration of 4a in mice suffering from experimental
autoimmune encephalitis ameliorates the severity of the clinical symptoms
in a CB1/CB2-dependent manner. Moreover, 4a produced
analgesic effects in a rodent model of acute inflammatory pain, which
was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced
by oxaliplatin. Given these evidence, 4a, as MGL selective
inhibitor, could represent a valuable lead for the future development
of therapeutic options for multiple sclerosis and chronic pain.