Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects

Abstract

2-Arachidonoylglycerol (2-AG) and anandamide are endocannabinoids that activate cannabinoid receptors CB1 and CB2. Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that, for anandamide, is mediated by fatty acid amide hydrolase (FAAH) and, for 2-AG, is thought to involve monoacylglycerol lipase (MAGL). FAAH inhibitors produce a select subset of the behavioral effects observed with CB1 agonists, intimating a functional segregation of endocannabinoid signaling pathways in vivo. Testing this hypothesis, however, requires specific tools to independently block anandamide and 2-AG metabolism. Here, we report a potent and selective inhibitor of MAGL, JZL184, that, upon administration to mice, raises brain 2-AG by 8-fold without altering anandamide. JZL184-treated mice exhibited a broad array of CB1-dependent behavioral effects, including analgesia, hypothermia, and hypomotility. These data indicate that 2-AG endogenously modulates several behavioral processes classically associated with the pharmacology of cannabinoids and point to overlapping and unique functions for 2-AG and anandamide in vivo.

Dual Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Blockade Produces THC-Like Morris Water Maze Deficits in Mice

“…Previous studies have found that genetic deletion of FAAH leads to 10-fold increases in whole brain AEA levels 1 and that treatment with 16 or 40 mg/ kg JZL184 produces approximately 7−8-fold increases in levels of 2-AG in whole brains. 18,19,37 The present results extend these findings by revealing increases in AEA and 2-AG levels in specific brain regions. CB 1 receptor activation by exogenously applied cannabinoids, such as THC, lacks the regional selectivity and rapid metabolism of endocannabinoids.…”

“…These finding are consistent with other results showing that full MAGL inhibition produces a more extensive subset of THC-like effects than that produced by full FAAH inhibition. 18 In contrast to these findings, performance in the object recognition task and acquisition of reference memory in the Morris water maze is enhanced in MAGL −/− mice. 34 We have also found here that 20 mg/kg JZL184 does not disrupt short-term spatial memory performance in FAAH +/+ mice.…”

Dynamic changes to the endocannabinoid system in models of chronic pain

“…The potency of this compound is markedly reduced (approx. 10-fold) in rat brain membranes [92], but a small number of reports detailing the antinociceptive efficacy of local administration of JZL184 in the rat have been published. Indeed, antinociceptive effects of intra-plantar administration of JZL184 have been described in both phases of the formalin model of inflammatory pain [94], and also in capsaicin-induced acute pain [95], with mechanisms involving both CB1 and CB2 receptors.…”

Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain

“…MGL is a serine hydrolase with a catalytic triad represented by Ser122, His269, and Asp239. 9 Inhibitors of 2-AG degradation have been developed such as the carbamate biphenyl-3-ylcarbamic acid cyclohexyl ester (URB602), 10−12 the tetrahydrolipstatin (S)-1-((2S,3S)-3-hexyl-4-oxooxetan-2-yl)tridecan-2-yl 2-formamidoacetate (OMDM169), 13 the 4-(bis-benzo [1,3]dioxol-5-ylhydroxy-methyl)piperidine-1-carboxylic acid 4-nitro-phenyl ester 1 (JZL184), 14 the ureidic 4-(bis(4-fluorophenyl)methyl)-piperazin-1-yl)(1H-1,2,4-triazol-1-yl)methanone 2 (SAR629), 15 and their analogue (4-(bis(benzo[d] [1,3]dioxol-5-yl)methyl)-piperidin-1-yl)(1H-1,2,4-triazol-1-yl)methanone 3 (JJKK-048). 16 Despite the variety of MGL inhibitors available, the structural diversity of chemical templates explored to date remains poor.…”