Total synthesis of 2-Arachidonylglycerol (2-Ara-Gl)

Han, Luning; Razdan, Raj K.

doi:10.1016/s0040-4039(99)00028-3

Cited by 24 publications

(16 citation statements)

References 8 publications

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“…The MAGL inhibitor JZL184 (Long et al, 2009a) and the FAAH inhibitor PF-3845 (Ahn et al, 2009) were synthesized in the Cravatt laboratory as described previously, and 2-arachidonoylglycerol was synthesized as described previously (Han and Razdan, 1999). All drugs were dissolved in a vehicle consisting of ethanol, Alkamuls-620 (Rhone-Poulenc, Princeton, NJ), and saline in a ratio of 1:1:18.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Monoacylglycerol Lipase Attenuates Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Hemorrhages in Mice

Kinsey

Nomura²,

O’Neal³

et al. 2011

J Pharmacol Exp Ther

106

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Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used analgesics, but can cause gastric and esophageal hemorrhages, erosion, and ulceration. The endogenous cannabinoid (endocannabinoid; eCB) system possesses several potential targets to reduce gastric inflammatory states, including cannabinoid receptor type 1 (CB 1 ), cannabinoid receptor type 2 (CB 2 ), and enzymes that regulate the eCB ligands 2-arachidonoylglycerol (2-AG) and N-arachidonoyl ethanolamine (anandamide; AEA). In the presented study, we tested whether 4-nitrophenyl, a selective inhibitor of the primary catabolic enzyme of 2-AG, monoacylglycerol lipase (MAGL), would protect against NSAID-induced gastric damage. Food-deprived mice administered the nonselective cyclooxygenase inhibitor diclofenac sodium displayed gastric hemorrhages and increases in proinflammatory cytokines. JZL184, the proton pump inhibitor omeprazole (positive control), or the primary constituent of marijuana, ⌬ 9 -tetrahydrocannabinol (THC), significantly prevented diclofenac-induced gastric hemorrhages. JZL184 also increased stomach levels of 2-AG, but had no effect on AEA, arachidonic acid, or the prostaglandins E 2 and D 2 . MAGL inhibition fully blocked diclofenac-induced increases in gastric levels of proinflammatory cytokines interleukin (IL)-1␤, IL-6, tumor necrosis factor ␣, and granulocyte colony-stimulating factor, as well as IL-10. Pharmacological inhibition or genetic deletion of CB 1 or CB 2 revealed that the gastroprotective effects of JZL184 and THC were mediated via CB 1 . The antihemorrhagic effects of JZL184 persisted with repeated administration, indicating a lack of tolerance. These data indicate that increasing 2-AG protects against gastric damage induced by NSAIDs, and its primary catabolic enzyme MAGL offers a promising target for the development of analgesic therapeutics possessing gastroprotective properties.

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Section: Methodsmentioning

confidence: 99%

Inhibition of Monoacylglycerol Lipase Attenuates Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Hemorrhages in Mice

Kinsey

Nomura²,

O’Neal³

et al. 2011

J Pharmacol Exp Ther

106

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“…Fatty acid amides were chemically synthesized as described previously (Cravatt et al, 1996). Monoacylglycerols were synthesized as described previously (Han and Razdan, 1999). All drugs were administered i.p.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological Activity of Fatty Acid Amides Is Regulated, but Not Mediated, by Fatty Acid Amide Hydrolase in Vivo

Lichtman

Hawkins²,

Griffin³

et al. 2002

J Pharmacol Exp Ther

212

139

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Fatty acid amides (FAAs) represent a class of neuromodulatory lipids that includes the endocannabinoid anandamide and the sleep-inducing substance oleamide. Both anandamide and oleamide produce behavioral effects indicative of cannabinoid activity, but only anandamide binds the cannabinoid (CB1) receptor in vitro. Accordingly, oleamide has been proposed to induce its behavioral effects by serving as a competitive substrate for the brain enzyme fatty acid amide hydrolase (FAAH) and inhibiting the degradation of endogenous anandamide. To test the role that FAAH plays as a mediator of oleamide activity in vivo, we have compared the behavioral effects of this FAA in FAAH(ϩ/ϩ) and (Ϫ/Ϫ) mice. In both genotypes, oleamide produced hypomotility, hypothermia, and ptosis, all of which were enhanced in FAAH(Ϫ/Ϫ) mice, were unaffected by the CB1 antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-di-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A) and occurred in CB1(Ϫ/Ϫ) mice. Additionally, oleamide displayed negligible binding to the CB1 receptor in brain extracts from either FAAH(ϩ/ϩ) or (Ϫ/Ϫ) mice. In contrast, anandamide exhibited a 15-fold increase in apparent affinity for the CB1 receptor in brains from FAAH(Ϫ/Ϫ) mice, consistent with its pronounced CB1-dependent behavioral effects in these animals. Contrary to both oleamide and anandamide, monoacylglycerol lipids exhibited equivalent hydrolytic stability and pharmacological activity in FAAH(ϩ/ϩ) and (Ϫ/Ϫ) mice. Collectively, these results indicate that FAAH is a key regulator, but not mediator of FAA activity in vivo. More generally, these findings suggest that FAAs represent a family of signaling lipids that, despite sharing similar chemical structures and a common pathway for catabolism, produce their behavioral effects through distinct receptor systems in vivo.

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“…26 The synthesis of an ether-linked analogue of 2-AG, 2-eicosatetraenylglycerol (2-AG-ether), has been detailed elsewhere. 17 The structure of all 3 compounds was confirmed by nuclear magnetic resonance and electron impact mass spectrometry.…”

Section: Drugsmentioning

confidence: 99%

Cardiovascular Effects of 2-Arachidonoyl Glycerol in Anesthetized Mice

et al. 2000

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Abstract-Cannabinoids, including the endogenous ligand anandamide, elicit pronounced hypotension and bradycardia through the activation of CB1 cannabinoid receptors. A second endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), has been proposed to be the natural ligand of CB1 receptors. In the present study, we examined the effects of 2-AG on mean arterial pressure and heart rate in anesthetized mice and assessed the role of CB1 receptors through the use of selective cannabinoid receptor antagonists and CB1 receptor knockout (CB1 Ϫ/Ϫ ) mice. In control ICR mice, intravenous injections of 2-AG or its isomer 1-AG elicit dose-dependent hypotension and moderate tachycardia that are unaffected by the CB1 receptor antagonist SR141716A. The same dose of SR141716A (6 nmol/g IV) completely blocks the hypotensive effect and attenuates the bradycardic effect of anandamide. 2-AG elicits a similar hypotensive effect, resistant to blockade by either SR141716A or the CB2 antagonist SR144528, in both CB1Ϫ/Ϫ mice and their homozygous (CB1 ϩ/ϩ ) control littermates. In ICR mice, arachidonic acid (AA, 15 nmol/g IV) elicits hypotension and tachycardia, and indomethacin (14 nmol/g IV) inhibits the hypotensive effect of both AA and 2-AG. Synthetic 2-AG incubated with mouse blood is rapidly (Ͻ2 minutes) and completely degraded with the parallel appearance of AA, whereas anandamide is stable under the same conditions. A metabolically stable ether analogue of 2-AG causes prolonged hypotension and bradycardia in ICR mice, and both effects are completely blocked by SR141716A, whereas the same dose of 2-AG-ether does not influence blood pressure and heart rate in CB1 Ϫ/Ϫ mice. These findings are interpreted to indicate that exogenous 2-AG is rapidly degraded in mouse blood, probably by a lipase, which masks its ability to interact with CB1 receptors. Although the observed cardiovascular effects of 2-AG probably are produced by an arachidonate metabolite through a noncannabinoid mechanism, the CB1 receptor-mediated cardiovascular effects of a stable analogue of 2-AG leaves open the possibility that endogenous 2-AG may elicit cardiovascular effects through CB1 receptors. (Hypertension. 2000;35:679-684.)

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Total synthesis of 2-Arachidonylglycerol (2-Ara-Gl)

Cited by 24 publications

References 8 publications

Inhibition of Monoacylglycerol Lipase Attenuates Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Hemorrhages in Mice

Inhibition of Monoacylglycerol Lipase Attenuates Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Hemorrhages in Mice

Pharmacological Activity of Fatty Acid Amides Is Regulated, but Not Mediated, by Fatty Acid Amide Hydrolase in Vivo

Cardiovascular Effects of 2-Arachidonoyl Glycerol in Anesthetized Mice

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