生物活性

• 描述FAAH (fatty acid amide hydrolase) is an intracellular membranebound enzyme that principally degrade the endocannabinoid anandamide. It utilizes unusual catalytic triad Ser-Ser-Lys to degrade and inactivate fatty acid amide family of signaling lipids, including the endogenous cannabinoid ligands N-arachidonoylethanolamine (Anandamide, AEA) and 2-arachidonoyl glycerol (2-AG). PF-3845 is an irreversible, highly efficacious and selective FAAH inhibitor with Ki value of 0.23μM. Preincubation with PF-3845 for 1h inhibited hFAAH activity for hydrolysis of its substrate AAMCA. Administration of PF-3845 at dose of 10mg/kg, i.p., for 1-24h inactivated FAAH in the brain of mice as judged by competitive activity-based protein profiling with the serine hydrolase-directed probe fluorophosphonate (FP)-rhodamine. PF-3845-treated mice (10 mg/kg, i.p.) also showed dramatic elevations in brain levels of AEA and other NAEs (N-pamitoyl ethanolamine [PEA] and N-oleoyl ethanolamine [OEA]. PF-3845-treated animals did not show changes in the levels of 2-AG in brain or liver, suggesting that distinct enzymes regulate this endocannabinoid in vivo. Administration of PF-3845 produced cannabinoid receptor-dependent reductions in inflammatory pain in vivo. Oral administration of PF-3845 at 10 and 30mg/kg caused a dose-dependent inhibition of mechanical allodynia and inhibited pain response in a rat model of inflammatory pain.
• 作用机制PF-3845 is a covalent inhibitor that carbamylates FAAH’s serine nucleophile.