ARN 272 is a a competitive antagonist of the interaction of anandamide with FAAH-like anandamide transporter (FLAT), that lacks amidase activity but binds anandamide with low micromolar affinity and facilitates its translocation into cells.
This FLAT inhibitor (FW = 432.47 g/mol; CAS 488793-85-7), also named 4-[[4-(4-hydroxy-phenyl)-1-phthalazinyl]amino]-N-phenylbenzamide, targets the FAAH-Like Anandamide Transporter (IC50 = 1.8 μM), a catalytically silent variant of fatty acid amide hydrolase-1 (FAAH-1) that drives anandamide transport. Mode of Action: The intensity and duration of anandamide signaling appear to be controlled by a two-step elimination process, in which the anandamide or an anandamide-like substance is first internalized by neurons and astrocytes through the action of FLAT and then undergoes hydrolysis through the action of the intracellular membrane- bound amidases, FAAH-1 and FAAH-2. ARN-272 attenuates anandamide internalization, thereby reducing its deactivation. ARN272 competitively antagonizes [ 3 H]-anandamide binding to FLAT (IC50 = 1.8 μM) and inhibits [ 3 H]-anandamide accumulation in both FLAT-expressing Hek293 cells (IC50 ≈ 3 μM) and primary cultures of cortical neurons prepared from rats or wild-type mice. By contrast, ARN272 is without significant effect on the residual [ 3 H]-anandamide accumulation observed in cortical transport system may also facilitate the release of this lipid mediator from cells It also exhibits analgesic effects in rodent models of CB1 endocannabinoid receptor-mediated nociceptive and inflammatory pain.
