Development of a potent inhibitor of 2-arachidonoylglycerol hydrolysis with antinociceptive activity in vivo

Bisogno, Tiziana; Ortar, Giorgio; Petrosino, Stefania; Morera, Enrico; Palazzo, Enza; Nalli, Marianna; Maione, Sabatino; Marzo, Vincenzo Di

doi:10.1016/j.bbalip.2008.10.007

Cited by 66 publications

(67 citation statements)

References 42 publications

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“…173 Interestingly, compound 158 exhibited varied inhibitory potency against MAGL according to the different enzyme sources and species. 174 In fact, compound 158 produced superior potency in rat brain and rat cerebellum rather than in the corresponding mouse tissues. 174 Compound 158 was detected to produce antinociception and elevate 2-AG levels without affecting AEA concentrations in mice pre-treated with 50 formalin.…”

Section: Other Magl Inhibitorsmentioning

confidence: 99%

“…174 In fact, compound 158 produced superior potency in rat brain and rat cerebellum rather than in the corresponding mouse tissues. 174 Compound 158 was detected to produce antinociception and elevate 2-AG levels without affecting AEA concentrations in mice pre-treated with 50 formalin. However, the elevation of 2-AG levels was only observed in the ipsilateral paw that influenced by the administration of formalin, but not in the contralateral paw.…”

Section: Other Magl Inhibitorsmentioning

confidence: 99%

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Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

et al. 2016

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Section: Other Magl Inhibitorsmentioning

confidence: 99%

Section: Other Magl Inhibitorsmentioning

confidence: 99%

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

et al. 2016

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“…These have led to the identification of several novel inhibitors of MAGL that produce cannabimimetic effects in vivo, including OMDM169 [91] and JZL184 [92]. JZL184 possesses high selectivity for MAGL over FAAH (.300-fold), HSL and other common off-target serine hydrolases and lipases, and shows a nanomolar potency in isolated mouse brain membranes [92].…”

Section: -Ag and Pain Processingmentioning

confidence: 99%

Dynamic changes to the endocannabinoid system in models of chronic pain

Sagar

Burston

Woodhams

et al. 2012

Phil. Trans. R. Soc. B

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The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling.

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“…98 (m, 1H), 1.93 (m, 2H), 1.51 (m, 1H). 13 trans-1-(1-(1H-1,2,4-Triazole-1-carbonyl)piperidin-4-yl)-4-(3,4-dimethoxyphenyl)-3-(4-methoxyphenyl)azetidin-2-one (4f). Title compound was obtained starting from 6c as described for compound (±)-4a.…”

Section: ■ Conclusionmentioning

confidence: 99%

“…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.…”

Section: ■ Introductionmentioning

confidence: 99%

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

et al. 2016

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We report the discovery of compound 4a, a potent β-lactam-based monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible and stereoselective mechanism of action, high membrane permeability, high brain penetration evaluated using a human in vitro blood-brain barrier model, high selectivity in binding and affinity-based proteomic profiling assays, and low in vitro toxicity. Mode-of-action studies demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol and behaves as a cannabinoid (CB1/CB2) receptor indirect agonist. Administration of 4a in mice suffering from experimental autoimmune encephalitis ameliorates the severity of the clinical symptoms in a CB1/CB2-dependent manner. Moreover, 4a produced analgesic effects in a rodent model of acute inflammatory pain, which was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced by oxaliplatin. Given these evidence, 4a, as MGL selective inhibitor, could represent a valuable lead for the future development of therapeutic options for multiple sclerosis and chronic pain

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Development of a potent inhibitor of 2-arachidonoylglycerol hydrolysis with antinociceptive activity in vivo

Cited by 66 publications

References 42 publications

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

Dynamic changes to the endocannabinoid system in models of chronic pain

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

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