Design of arylfurans as potential FAAH inhibitors: therapeutic potential in pain management

The endocannabinoid system plays a critical role in regulating pathophysiological processes and represents a promising target for novel therapies aimed at neurodegenerative disorders. Anandamide (AEA) mediates its therapeutic effects, particularly in pain modulation; however, its clinical potential is constrained by rapid degradation via fatty acid amide hydrolase (FAAH). The keto-oxazolopyridine derivative OL-135 is a potent FAAH inhibitor (IC₅₀ = 4.7 nM). In this study, molecular docking simulations using three distinct protocols were performed to evaluate the binding modes of 44 arylfuran analogs of OL-135 at the FAAH enzyme binding site. These analyses identified several promising candidates, including analogs 2 and 24, which were subsequently synthesized, characterized, and tested in experimental models of pain and inflammation in mice. Carrageenan-induced pain and paw edema were used to investigate the antinociceptive and anti-inflammatory activities. Also, hot plate test was employed to evaluate the antinociceptive activity. Compound 2 significantly reduced mechanical allodynia and acute paw edema induced by carrageenan. Compounds 2 and 24 (5, 25 and 100 mg/Kg, i.p.) reduced the nociceptive response in model of nociceptive pain (hot plate). The activity of compound 2 (100 mg/Kg) in the model of nociceptive pain was attenuated by previous administration of AM251 (4 and 8 mg/Kg, i.p.). Importantly, compound 2 demonstrated no adverse effects on key biochemical parameters indicative of cardiotoxicity, hepatotoxicity, or nephrotoxicity. These findings underscore the potential of arylfuran analogs as analgesic and anti-inflammatory agents, paving the way for further development of therapeutic molecules.