Monoacylglycerol lipase (MAGL) is a 33 kDa membrane-related member of serine hydrolase superfamily. Besides, it contains the classical GXSXG common sequence common to most serine hydrolases. MAG is the main enzyme responsible for inactivating the most abundant brain endogenous cannabinoid 2-arachidonic acid glycerin (2-AG). Moreover, MAGL not only controls the in vivo level of 2-AG but also controls the in vivo level of other monoacylglycerides. Furthermore, MAGL indirectly controls the level of free fatty acids produced by its hydrolysis, as well as other lipids with pro-inflammatory or pro-tumor effects. The hydrolysis of 2-AG catalyzed by MAGL leads to the formation of arachidonic acid (AA), which constitutes the precursor of arachidonic acid. Meanwhile, MAGL-mediated hydrolysis of monoacylglycerol in adipose tissue and liver leads to the production of free fatty acids.

Specifically, ARS2 regulates stem cell-like characteristics of GSCs through direct transcriptional activation of MAGL. ARS2-MAGL signal is induced by β- The accumulation of catenin activates self-renewal. Nonetheless, MAGL is relevant to pathological conditions such as pain, inflammation, and neurodegenerative diseases. Importantly, MAGL plays a key role in the development and spread of cancer. MAGL has attracted more and more attention as a promising drug target. Today, we will introduce a potent and reversible inhibitor of MAGL, JZP-361.

JZP-361 is a Potent and Reversible MAGL Inhibitor.

Above all, JZP-361 is a potent and reversible inhibitor of human recombinant MAGL (hMAGL, IC₅₀=46 nM). Particularly, JZP-361 has almost 150-fold higher selectivity over human recombinant fatty acid amide hydrolase (hFAAH, IC₅₀=7.24 μM). Obviously, JZP-361 has 35-fold higher selectivity over human α/β-hydrolase-6 (hABHD6, IC₅₀=1.79 μM).

Next in importance, JZP-361 represents a dual-acting pharmacological tool possessing both MAGL inhibitory and antihistaminic activities. Additionally, JZP-361 exhibits no activity at the cannabinoid CB1 and CB2 receptors.

All in all, JZP-361 is a potent and reversible inhibitor of MAGL with  anti-histaminergic activities.

References:

Jayendra Z Patel, et al. Bioorg Med Chem Lett. 2015 Apr 1;25(7):1436-42.