β-lactams to act on the endocannabinoid system

Morelle, Axel [UCL] Caruano, Joséphine [UCL] Feledziak, Marion [UCL] Michaux, Catherine [UNamur] Perpète, Eric [UNamur] Muccioli, Giulio [UCL] Marchand-Brynaert, Jacqueline [UCL] Robiette, Raphaël [UCL]

(eng) Anandamide (2) is a lipid mediator involved in the activation of the cannabinoid receptors CB1 and CB2. Since the activation of these receptors results in a myriad of therapeutic effects (analgesic, anti-inflammatory, Stimulation of sleep, regulation of appetite,...), a prolonged action of anandamide is often desirable. The best way to achieve this goal consists in the inhibition of the main endocannabinoid-degrading enzyme, Fatty Acid Amide Hydrolase (FAAH). Our laboratory discovered that some β-lactams have an inhibition activity on FAAH. A very promising lead (6h) with an IC 50 of 4.2 nM was obtained during these studies. Pharmacological studies enabled us to show that these β-lactams are reversible inhibitors. We have demonstrated by HPLC-MS that FAAH doesn’t cleave the β-lactam cycle, suggesting the absence of covalent bonding between the β-lactam and the enzyme. Finally, SAR and docking studies provided insights into the structure and the nature of the interactions involved in the inhibitor-enzyme complex.