Highly Selective Inhibitors of Monoacylglycerol Lipase Bearing a Reactive Group that Is Bioisosteric with Endocannabinoid Substrates

Chang, Jae Won; Niphakis, Micah J.; Lum, Kenneth M.; Cognetta, Armand B.; Wang, Chu; Matthews, Megan L.; Niessen, Sherry; Buczynski, Matthew W.; Parsons, Loren H.; Cravatt, Benjamin F.

doi:10.1016/j.chembiol.2012.03.009

Cited by 163 publications

(204 citation statements)

References 39 publications

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“…In peripheral tissues, JZL184, like many other carbamate agents, also blocked the activity of multiple CES enzymes (Long et al, 2009b). Very recently, next-generation MAGL inhibitors based on an O-hexafluoroisopropyl carbamate scaffold have been developed that possess superior selectivity toward MAGL versus other serine hydrolases in the brain and peripheral tissues (Chang et al, 2012). The O-hexafluoroisopropyl analog of JZL184, KML29 (Fig.…”

Section: Endocannabinoid Hydrolase Inhibitorsmentioning

confidence: 99%

Chemical Probes of Endocannabinoid Metabolism

2013

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Section: Endocannabinoid Hydrolase Inhibitorsmentioning

confidence: 99%

Chemical Probes of Endocannabinoid Metabolism

2013

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“…MJN110 was synthesized in the Cravatt Laboratory at the Scripps Research Institute as described previously (Chang et al, 2012;Niphakis et al, 2013). The CB 1 receptor antagonist rimonabant…”

Section: Methodsmentioning

confidence: 99%

The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model

Wilkerson

Niphakis

Grim

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Serious clinical liabilities associated with the prescription of opiates for pain control include constipation, respiratory depression, pruritus, tolerance, abuse, and addiction. A recognized strategy to circumvent these side effects is to combine opioids with other antinociceptive agents. The combination of opiates with the primary active constituent of cannabis (D 9 -tetrahydrocannabinol) produces enhanced antinociceptive actions, suggesting that cannabinoid receptor agonists can be opioid sparing. Here, we tested whether elevating the endogenous cannabinoid 2-arachidonoylglycerol through the inhibition of its primary hydrolytic enzyme monoacylglycerol lipase (MAGL), will produce opioid-sparing effects in the mouse chronic constriction injury (CCI) of the sciatic nerve model of neuropathic pain. The dose-response relationships of i.p. administration of morphine and the selective MAGL inhibitor 2,5-dioxopyrrolidin-1-yl 4-(bis (4-chlorophenyl)methyl)piperazine-1-carboxylate (MJN110) were tested alone and in combination at equieffective doses for reversal of CCI-induced mechanical allodynia and thermal hyperalgesia. The respective ED 50 doses (95% confidence interval) of morphine and MJN110 were 2.4 (1.9-3.0) mg/kg and 0.43 (0.23-0.79) mg/kg. Isobolographic analysis of these drugs in combination revealed synergistic antiallodynic effects. Acute antinociceptive effects of the combination of morphine and MJN110 required m-opioid, CB 1 , and CB 2 receptors. This combination did not reduce gastric motility or produce subjective cannabimimetic effects in the drug discrimination assay. Importantly, combinations of MJN110 and morphine given repeatedly (i.e., twice a day for 6 days) continued to produce antiallodynic effects with no evidence of tolerance. Taken together, these findings suggest that MAGL inhibition produces opiate-sparing events with diminished tolerance, constipation, and cannabimimetic side effects.

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“…In comparison, JZL184 has been reported to inhibit 75% of mouse brain MAGL at a dose of 4 mg/kg, whereas a dose of 16 mg/kg resulted in nearly complete inhibition of MAGL (Long et al, 2009a). With KML29, partial inhibition of MAGL was achieved with a dose of 5 mg/kg and maximal inhibition with 20 mg/kg (Chang et al, 2012). Thus, JJKK-048 exhibits superior in vivo potency compared with JZL184 and KML29.…”

Section: Discussionmentioning

confidence: 91%

“…Previously, JZL184 was demonstrated to have cross-reactivity with 50-65 kDa carboxylesterase (CES) enzymes in peripheral tissues (Long et al, 2009b;Chang et al, 2012). KML29 represented improved selectivity against CESs and only with high doses (20-40 mg/kg) blocked peripheral ∼70-kDa enzyme, which was postulated to correspond to carboxylesterase 1 (ES1) (Chang et al, 2012). Due to structural similarities between KML29 and JJKK-048, it is likely that ES1 is also the peripheral off-target of JJKK-048 in mouse tissues in the present study.…”

Section: Jjkk-048 Potently Inhibits Magl and Elevatesmentioning

confidence: 99%

“…The sulfhydryl reagent N-arachidonoylmaleimide (Saario et al, 2005;Burston et al, 2008) and a carbamate compound biphenyl-3-ylcarbamic acid cyclohexyl ester (URB602) (Hohmann et al, 2005) were among the first compounds showing activity in vivo, but their potency and MAGL selectivity were proved to be insufficient. More recently, the carbamate compounds 4-nitrophenyl 4-(dibenzo [d] [1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) (Long et al, 2009a) and its derivative 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(benzo[d] [1,3]dioxol-5-yl)(hydroxy) methyl) piperidine-1-carboxylate (KML29) (Chang et al, 2012) were reported as selective MAGL inhibitors that increase brain 2-AG levels and display a more restricted set of behavioral effects when compared with the CB 1 agonists or the dual MAGL and FAAH inhibitors. Carbamate-based inhibitors typically inactivate serine hydrolases by an irreversible covalent modification (carbamoylation) of the catalytic serine nucleophile (Bar-On et al, 2002;Alexander and Cravatt, 2005).…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Characterization of the Ultrapotent Monoacylglycerol Lipase Inhibitor (1H-1,2,4-triazol-1-yl)methanone (JJKK-048)

Aaltonen

Kędzierska

Orzelska‐Górka

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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In Vivo Characterization of the Ultrapotent Monoacylglycerol Lipase Inhibitor {4- [bis-(benzo[d] [1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone Niina Aaltonen, Ewa Kedzierska, Jolanta Orzelska-Górka, Marko Lehtonen, Dina Navia-Paldanius, Hermina Jakupovic, Juha R. Savinainen, Tapio Nevalainen, Jarmo T. Laitinen, Teija Parkkari, and Mikko Gynther ABSTRACT Monoacylglycerol lipase (MAGL) is a serine hydrolase that acts as a principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). In addition to terminating the signaling function of 2-AG, MAGL liberates arachidonic acid to be used as a primary source for neuroinflammatory prostaglandin synthesis in the brain. MAGL activity also contributes to cancer pathogenicity by producing precursors for tumor-promoting bioactive lipids. Pharmacological inhibitors of MAGL provide valuable tools for characterization of MAGL and 2-AG signaling pathways. They also hold great therapeutic potential to treat several pathophysiological conditions, such as pain, neurodegenerative disorders, and cancer. We have previously reported piperidine triazole urea, {4-[bis- , to be an ultrapotent and highly selective inhibitor of MAGL in vitro. Here, we characterize in vivo effects of JJKK-048. Acute in vivo administration of JJKK-048 induced a massive increase in mouse brain 2-AG levels without affecting brain anandamide levels. JJKK-048 appeared to be extremely potent in vivo. Activity-based protein profiling revealed that JJKK-048 maintains good selectivity toward MAGL over other serine hydrolases. Our results are also the first to show that JJKK-048 promoted significant analgesia in a writhing test with a low dose that did not cause cannabimimetic side effects. At a high dose, JJKK-048 induced analgesia both in the writhing test and in the tail-immersion test, as well as hypomotility and hyperthermia, but not catalepsy. IntroductionEndocannabinoids are lipid-structured signaling molecules that act as natural ligands for cannabinoid CB 1 and CB 2 receptors, which are also the targets of the psychoactive component of Cannabis sativa. The two most intensively studied endocannabinoids are 2-arachidonoylglycerol (2-AG) and anandamide (AEA) (Devane et al., 1992;Mechoulam et al., 1995;Sugiura et al., 1995). Generally, endocannabinoids are synthesized on demand from plasma membrane phospholipid precursors, and after exerting their effect by activating specific receptors, they are rapidly degraded by enzymatic activity. The principal brain endocannabinoid is 2-AG, which regulates central nervous system development and synaptic plasticity (Bisogno et al., 1999;Berghuis et al., 2007;Hashimotodani et al., 2007). Endocannabinoids also regulate cognition, emotional functions, and food intake, and are involved in several pathophysiological processes, including pain and neurodegenerative diseases (Pacher et al., 2006;Di Marzo and Petrosino, 2007;Sugiura, 2009). However, for therapeutic purposes, direct activation of cannabinoid receptors has proved to be c...

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Highly Selective Inhibitors of Monoacylglycerol Lipase Bearing a Reactive Group that Is Bioisosteric with Endocannabinoid Substrates

Cited by 163 publications

References 39 publications

Chemical Probes of Endocannabinoid Metabolism

Chemical Probes of Endocannabinoid Metabolism

The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model

In Vivo Characterization of the Ultrapotent Monoacylglycerol Lipase Inhibitor (1H-1,2,4-triazol-1-yl)methanone (JJKK-048)

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