- Novel, regioselective transformation of an oxirane system. An efficient approach to the synthesis of endocannabinoid 2-arachidonoylglycerol
-
A trifluoroacetic anhydride-catalysed opening of the oxirane system of glycidyl arachidonate with a simultaneous migration of the acyl group provides a new, efficient entry to 2-arachidonoylglycerol.
- Stamatov, Stephan D.,Stawinski, Jacek
-
-
Read Online
- Total synthesis of 2-arachidonylglycerol (2-Ara-Gl)
-
Total synthesis of 2-Arachidonylglycerol (2-Ara-Gl) was accomplished starting from arachidonic acid and glycerol. The sequence involves selective protection of the primary alcohols of glycerol, esterification, and mild hydrolysis of the protecting groups. A unique hydrolysis condition was developed to prevent isomerization of the 2-Ara-Gl to the more stable 1- monoglyceride.
- Han, Luning,Razdan, Raj K.
-
-
Read Online
- Facile synthesis and stabilization of 2-arachidonylglycerol via its 1,3- phenylboronate ester
-
2-Arachidonylglycerol (2-Ara-Gl) was synthesized via the intermediacy of its 1,3-phenylboronic acid ester. The boronate ester is easily stable enough to enable chromatographic resolution from the corresponding 1-Ara-Gl boronate ester on normal phase elution yet immediately and completely hydrolyzes to 2- Ara-G1 and phenylboronic acid, without isomerization, by simple solution in aqueous-organic solvents. The phenylboronate ester of this 2-acylglycerol has the added advantage of being markedly more stable to both isomerization and oxidation upon storage than the labile 2-Ara-Gl. (C) 2000 Elsevier Science Ltd.
- Seltzman, Herbert H.,Fleming, Denise N.,Hawkins, Gregory D.,Carroll, F. Ivy
-
-
Read Online
- Photorelease of 2-Arachidonoylglycerol in Live Cells
-
2-Arachidonoylglycerol (2-AG) is acting as a full agonist of cannabinoid receptor 1 and 2. Direct manipulation of 2-AG levels is a challenging task. The amphiphilic properties and the instability of 2-AG in aqueous media complicate its use as a drug-like molecule. Additionally, inhibition of the protein machinery that regulates 2-AG levels may also affect other monoacylglycerols. Therefore, we developed a novel method to elevate 2-AG levels with a flash of light. The resulting tool is a photoactivatable "caged" 2-arachidonoylglycerol (cg2-AG) allowing for the rapid photorelease of the signaling lipid in live cells. We characterized the mechanism of uncaging and the effect of 2-AG on the regulation of the β-cell signaling network. After uncaging of 2-AG, we monitored calcium levels, CB1-GIRK channel coupling, and CB1-mediated inhibition of adenylate cyclase and protein kinase A activity.
- Laguerre, Aurélien,Hauke, Sebastian,Qiu, Jian,Kelly, Martin J.,Schultz, Carsten
-
-
Read Online
- Highly Selective, Reversible Inhibitor Identified by Comparative Chemoproteomics Modulates Diacylglycerol Lipase Activity in Neurons
-
Diacylglycerol lipase (DAGL)-α and -β are enzymes responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Selective and reversible inhibitors are required to study the function of DAGLs in neuronal cells in an acute and temporal fashion, but they are currently lacking. Here, we describe the identification of a highly selective DAGL inhibitor using structure-guided and a chemoproteomics strategy to characterize the selectivity of the inhibitor in complex proteomes. Key to the success of this approach is the use of comparative and competitive activity-based proteome profiling (ABPP), in which broad-spectrum and tailor-made activity-based probes are combined to report on the inhibition of a protein family in its native environment. Competitive ABPP with broad-spectrum fluorophosphonate-based probes and specific β-lactone-based probes led to the discovery of α-ketoheterocycle LEI105 as a potent, highly selective, and reversible dual DAGL-α/DAGL-β inhibitor. LEI105 did not affect other enzymes involved in endocannabinoid metabolism including abhydrolase domain-containing protein 6, abhydrolase domain-containing protein 12, monoacylglycerol lipase, and fatty acid amide hydrolase and did not display affinity for the cannabinoid CB1 receptor. Targeted lipidomics revealed that LEI105 concentration-dependently reduced 2-AG levels, but not anandamide levels, in Neuro2A cells. We show that cannabinoid CB1-receptor-mediated short-term synaptic plasticity in a mouse hippocampal slice model can be reduced by LEI105. Thus, we have developed a highly selective DAGL inhibitor and provide new pharmacological evidence to support the hypothesis that "on demand biosynthesis" of 2-AG is responsible for retrograde signaling.
- Baggelaar, Marc P.,Chameau, Pascal J. P.,Kantae, Vasudev,Hummel, Jessica,Hsu, Ku-Lung,Janssen, Freek,Van Der Wel, Tom,Soethoudt, Marjolein,Deng, Hui,Den Dulk, Hans,Allarà, Marco,Florea, Bogdan I.,Di Marzo, Vincenzo,Wadman, Wytse J.,Kruse, Chris G.,Overkleeft, Herman S.,Hankemeier, Thomas,Werkman, Taco R.,Cravatt, Benjamin F.,Van Der Stelt, Mario
-
supporting information
p. 8851 - 8857
(2015/07/27)
-
- Application of chemoenzymatic hydrolysis in the synthesis of 2-monoacylglycerols
-
The selective biocatalyzed synthesis of 2-monoacylglycerols (2-MAGs) through the use of commercially available immobilized Candida antarctica (Novozym435) and Rhizomucor miehei is explored. Reactions at room temperature result in the formation of a 2-MAG and a corresponding ethyl ester of the fatty acid with immobilized C. antarctica within 2 h with yields ranging from 36% to 83%. Similar reaction conditions with immobilized R. miehei yielded exclusively the 2-MAG after 24 h with yields ranging from 37% to 88%. Yields vary on the acyl group at the sn-2 position and choice of enzyme involved.
- Whitten, Kyle M.,Makriyannis, Alexandros,Vadivel, Subramanian K.
-
experimental part
p. 5422 - 5428
(2012/09/08)
-
- Mild acetal cleavage using B-chlorocatecholborane in the synthesis of rearrangement-sensitive 2-arachidonoylglycerol
-
A mild method for the cleavage of an acetal to afford a rearrangement sensitive diol using B-chlorocatecholborane was developed for the synthesis of the endogenous cannabinoid neurochemical messenger 2-arachidonoylglycerol. The tendency for rearrangement of 2-arachidonoylglycerol to the corresponding 1-arachidonoylglycerol was precluded with this reagent. Features of the partial recyclization to an isomeric acetal provide mechanistic detail.
- Roche, Michael J.,Madren, Seth M.,Tallent, C. Ray,Carroll, F. Ivy,Seltzman, Herbert H.
-
experimental part
p. 3825 - 3827
(2012/08/28)
-
- Chemoenzymatic synthesis of 2-arachidonoylglycerol, an endogenous ligand for cannabinoid receptors
-
A simple and efficient synthesis of 2-arachidonoyl glycerol, an endogenous agonist for cannabinoid receptors was achieved using Novozym 435, immobilized lipase from Candida antarctica.
- Vadivel, Subramanian K.,Whitten, Kyle M.,Makriyannis
-
scheme or table
p. 1149 - 1150
(2011/03/21)
-
- A methodology for radiolabeling of the endocannabinoid 2- arachidonoylglycerol (2-AG)
-
The metabolic intermediate and endocannabinoid signaling lipid 2-arachidonoylglycerol (2-AG) has not been readily labeled, primarily because of its instability toward rearrangement. We now detail a synthetic method that easily gives tritiated 2-AG from [5,6,8,9,11,12,14,15-3H(N)] arachidonic acid in two steps. We utilized a short chain 1,3-diacylglycerol and proceeded through the "structured lipid" [5′′, 6′′,8′′,9′′,11′′, 12′′,14′′,15′′-3H(N)]2- arachidonoyl-1,3-dibutyrylglycerol, a triacylglycerol that was conveniently deprotected in ethanol with acrylic beads containing Candida antarctica lipase B to give [5′′,6′′,8′′,9′′, 11′′,12′′,14′′,15′′- 3H(N)]2-arachidonoylglycerol ([3H]2-AG). The flash chromatographic separation necessary to isolate the labeled 2-acylglycerol [3H]2-AG resulted in only 4% of the rearrangement byproducts that have been a particular problem with previous methodologies. This reliable "kit" method to prepare the radiolabeled endocannabinoid as needed gave tritiated 2-arachidonoylglycerol [3H]2-AG with a specific activity of 200 Ci/mmol for enzyme assays, metabolic studies, and tissue imaging. It has been run on unlabeled materials on over 10 mg scales and should be generally applicable to other 2-acylglycerols.
- Duclos, Richard I.,Johnston, Meghan,Vadivel, Subramanian K.,Makriyannis, Alexandros,Glaser, Sherrye T.,Gatley, S. John
-
experimental part
p. 2049 - 2055
(2011/06/19)
-
- Regioselective opening of an oxirane system with trifluoroacetic anhydride. A general method for the synthesis of 2-monoacyl- and 1,3-symmetrical triacylglycerols
-
A trifluoroacetic anhydride-catalyzed opening of the oxirane system of glycidyl esters with a simultaneous migration of the acyl group provides a new, efficient entry to either 2-monoacylglycerols (2-MAG) or 1,3-symmetrical triglycerides (1,3-STG) as potential prodrug frameworks.
- Stamatov, Stephan D.,Stawinski, Jacek
-
p. 3659 - 3669
(2007/10/03)
-
- Simplified chemical and radiochemical synthesis of 2-arachidonoyl-glycerol, an endogenous ligand of cannabinoid receptors
-
Endocannabinoids have emerged as a new class of lipid mediators, with manifold roles in the central nervous system and in the periphery. Several studies have identified 2-arachidonoyl-glycerol (2-AG) as a major endogenous agonist of cannabinoid receptors. Here, the chemical synthesis of 2-AG is reported, along with the synthesis of its tritium-labeled derivative. These unlabeled and radiolabeled compounds are suitable tools for unravelling some metabolic routes and biological activities of 2-AG in various cells and tissues.
- Cartoni, Antonella,Margonelli, Andrea,Angelini, Giancarlo,Finazzi-Agrò, Alessandro,Maccarrone, Mauro
-
p. 2723 - 2726
(2007/10/03)
-
- Synthesis and biological activities of 2- arachidonoylglycerol, an endogenous cannabinoid receptor ligand, and its metabolically stable ether-linked analogues
-
We synthesized 2-arachidonoylglycerol (1), an endogenous cannabinoid receptor ligand, and its metabolically stable ether- linked analogues. Compound 1 was synthesized from 1,3- benzylideneglycerol (6) and arachidonic acid in the presence of N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine followed by treatment with boric acid and trimethyl borate. An ether-linked analogue of 2-arachidonoylglycerol (2) was synthesized from 6 and 5,8,11,14-eicosatetraenyl iodide (9). The ether-linked analogues of 2-palmitoylglycerol (4) and 2- oleoyglycerol (5) were synthesized from 6 and hexadecyl iodide (12) and 9-octadecenyl iodide (14), respectively. We confirmed that 1 stimulates NG108-15 cells to induce rapid transient elevation of the intracellular free Ca2+ concentrations through a CB1 receptor-dependent mechanism. Noticeably, 2 exhibited appreciable agonistic activity, although its activity was significantly lower than that of 1. Compound 2 would be a useful tool in exploring the physiological significance of 1, because this compound is resistant to hydrolyzing enzymes in contrast to 1. On the other hand, the ether-linked analogues of either 4 or 5 failed to act as a CB1 receptor agonist. Compounds 4 and 5 would also be valuable as control molecules in experiments where 2 is employed.
- Suhara, Yoshitomo,Takayama, Hiroaki,Nakane, Shinji,Miyashita, Tomoyuki,Waku, Keizo,Sugiura, Takayuki
-
p. 903 - 907
(2007/10/03)
-
- Biologically active lipids binding membrane receptors
-
Neutral lipids are provided characterized by binding to phorboid and ingenoid receptors. These lipids are found in a wide variety of cellular sources as well as milk and may be isolated by specific extraction and chromatographic procedures. Depending upon the source, the glycerides may be mono- or di-glycerides, wherein the total number of carbon atoms of the fatty acids is in the range of 18 to 26, so that the monoglyceride has a fatty acid of at least 18 carbon atoms, while the di-glyceride has a fatty acid of at least 14 carbon atoms.
- -
-
-
