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

Abstract

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

Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages

“…Protein and ligands preparation : All ligands were built and treated by means of Maestro software as described previously . The compounds were filtered for pan‐assay interference compounds (PAINS).…”

“…Protein and ligands preparation:A ll ligands were built and treated by means of Maestro [25] software as described previously. [26][27][28] The compounds were filtered for pan-assay interference compounds (PAINS). None of them contained sub-structural features that would label them as "frequent hitters" in high-throughput screens.…”

Effects of a water extract of Lepidium meyenii root in different models of persistent pain in rats

“…for five consecutive days every week for 2 weeks (10 i.p. injections) [30,31]. Oxaliplatin was dissolved in 5% glucose solution.…”

Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain

“…The various FAAH inhibitors developed so far can be clustered into two families: irreversible (e.g., carbamates 1 a and 1 b , Figure ) and reversible inhibitors (e.g., α‐ketooxazole 2 , Figure ). In this context, we recently reported the development of different classes of compounds as inhibitors of EC metabolic enzymes: potent and selective FAAH or MAGL inhibitors and dual FAAH/MAGL inhibitors useful in different pathological states …”

“…[18] In proximity to the nucleophilic S241 residue, the oxyanion hole accommodates the carbonyl oxygen atom of amide or ester substrates by establishing hydrogen bonds.T he variousF AAH inhibitors developed so far can be clustered into two families: irreversible (e.g.,c arbamates 1a [19] and 1b, [20] Figure1)a nd reversible inhibitors (e.g., a-ketooxazole 2, [21] Figure1). In this context,w er ecently reported the developmento fd ifferent classes of compounds as inhibitors of EC metabolic enzymes: potent and selectiveF AAH [22][23] or MAGL [24] inhibitors and dual FAAH/MAGL [25] inhibitors useful in different pathological states. [26][27] As ac ontinuationo fo ur efforts in the discoveryo fF AAH inhibitors,h erein we describe the development of pyrrole-based analogues inspired by our previously identified ligands.…”