DO34

DO34 is a selective DAGL inhibitor, with an IC₅₀ of 6 nM for DAGLα conversion of SAG to 2-AG. DO34 blocks de novo 2-AG synthesis, and suppresses tonic CB₁ receptor activation. DO34 blocks depolarization-induced suppression of excitation and inhibition in the cerebellum and hippocampus. DO34 regulates feeding behavior and locomotor activity in mice. DO34 abolishes AM251-mediated enhancement of parallel fiber-evoked excitatory postsynaptic currents in cerebellar slices from MAGL global knockout mice. DO34 can be used for the research of energy balance disorder and neuroinflammation^[1][2][3]. IC50 & Target:IC50: 6 nM (DAGLα), 3-8 nM (DAGLβ)^[1]. In Vitro:DO34 (compound 5) potently inhibits both recombinant human DAGL enzymes in a SAG hydrolysis assay and endogenous DAGL enzymes in the mouse brain membrane proteome via activity-based protein profiling (ABPP) using DH379 or HT-01 probes, with pIC₅₀ values ranging from 8.2 to 9.3 for DAGLα and from 8.1 to 8.6 for DAGLβ. In Vivo:DO34 (compound 39) (50 mg/kg; i.p.; single dose) completely blocks fasting-induced refeeding in mice over the first 4 hours, alters carbohydrate and fat oxidation, and reduces locomotor activity^[1].
DO34 (50 mg/kg; i.p.; single dose) markedly reduces brain 2-AG levels, inhibits tonic CB₁ receptor activation, and blocks depolarization-induced suppression of excitation (DSE) and inhibition (DSI) in mice^[1][2].
DO34 (compound 5) (50 mg/kg; i.p.; single dose) attenuates LPS-induced neuroinflammation and anapyrexia in mice^[3].