Description
Endocannabinoids such as 2-
arachidonoyl glycerol (2-
AG) and arachidonoyl ethanolamide are biologically active lipids that are involved in a number of synaptic processes including activation of cannabinoid receptors. Monoacylglycerol lipase (MAGL) is a serine hydrolase responsible for the hydrolysis of 2-
AG to arachidonic acid and glycerol, thus terminating its biological function. KML29 is an O-
hexafluoroisopropyl carbamate analog of JZL 184 that potently and selectively inhibits MAGL (IC
50s = 15, 43, and 5.9 nM in mouse, rat, and human brain proteomes, respectively) over FAAH (IC
50s >50 μM). At 5-
20 mg/kg, KML29 dose-
dependently blocks mouse brain MAGL activity
in vivo, without any measurable effect on FAAH activity. As a second generation MAGL inhibitor, KML29 supersedes the low-
level cross reactivity that JZL 184 displays for FAAH yet still maintains comparable potency to its parent compound.
Uses
KML-29 is an extremely specific monoacylglycerol lipase (MAGL) inhibitor. KML-2 should be useful to distinguish between actions of 2-arachidonoyl glycerol (an endogenous ligand of cannabinoid receptors that is deactivated by MAGL) and anandamide, another endocannabinoid.
