LY-2183240

LY2183240 inhibits anandamide uptake in live cell with IC50 of 0.27 nM. ^[1] LY2183240 inactivates FAAH by carbamylation of the enzyme’s serine nucleophile. LY2183240 also inhibits KIAA1363, α/β-hydrolase 6 (Abh6) and monoacylglycerol lipase (MAG lipase) expressed in COS-7 cells with IC50 of 8.3, 0.09 and 5.3 nM, respectively. ^[2]

FAAH activity is measured in mouse brain membranes in the presence of varying concentrations of inhibitor. Brain membranes (1 mg/mL) from FAAH (-/-) mice are used as a control. Briefly, varying concentrations of LY2183240 (1 μL, 100×stock in DMSO added to provide 0.001-10 μM final concentration) are preincubated with brain membranes (1 mg/mL in 50 mM Tris, pH 8, 94 μL) for 10 min.

LY2183240 (i.p.) results in a dose-dependent increase in anandamide concentrations in rat cerebellum with ED50 of 1.37 mg/kg. LY2183240 (i.p.) dose-dependently attenuates formalin-induced paw-licking pain behavior in the formalin model of persistent pain mechanisms. ^[1] LY2183240 (10 mg/kg, i.p.) treatment for 90 min inactivates FAAH (100% inhibited), Abh6 (>90% inhibited), and MAG lipase (>60% inhibited) in brain tissue. ^[2] LY2183240 shows beneficiation on fear-potentiated startle (FPS) and alcohol-seeking behaviors (HAP) in mice selectively bred for high alcohol preference. Repeated administration of LY2183240 (30 mg/kg) reduces the expression of FPS in HAP mice when given prior to a second FPS test 48 h after fear conditioning. Both the 10 and 30 mg/kg doses of LY2183240 enhances the expression of alcohol-induced conditioned place preference and this effect persisted in the absence of the drug. ^[3]