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2-Arachidonoylglycerol
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Takayuki Sugiura – One of the best experts on this subject based on the ideXlab platform.
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Physiological roles of 2‐arachidonoylglycerol, an endogenous cannabinoid receptor ligand
BioFactors (Oxford England), 2009Co-Authors: Takayuki SugiuraAbstract:2-Arachidonoylglycerol is an arachidonic acid-containing monoacylglycerol isolated from the rat brain and canine gut as an endogenous ligand for the cannabinoid receptors (CB1 and CB2). 2-Arachidonoylglycerol binds to both the CB1 receptor, abundantly expressed in the nervous system, and the CB2 receptor, mainly expressed in the immune system, with high affinity, and exhibits a variety of cannabimimetic activities. Notably, anandamide, another endogenous ligand for the cannabinoid receptors, acts as a partial agonagonist at these cannabinoid receptors, whereas 2-Arachidonoylglycerol acts as a full agonist. The results of structure-activity relationship experiments strongly suggested that 2-Arachidonoylglycerol rather than anandamide is the true natural ligand for both the CB1 and the CB2 receptors. Evidence is gradually accumulating which shows that 2-Arachidonoylglycerol plays physiologically and pathophysiologically essential roles in various mammalian tissues and cells.
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2-Arachidonoylglycerol Enhances the Phagocytosis of Opsonized Zymosan by HL-60 Cells Differentiated into Macrophage-Like Cells
Biological & pharmaceutical bulletin, 2007Co-Authors: Maiko Gokoh, Saori Oka, Seishi Kishimoto, Takayuki SugiuraAbstract:2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). While evidence is accumulating that the CB1 receptor plays important regulatory roles in various nervous tissues and cells, the physiological roles of the CB2 receptor, which is abundantly expressed in the immune system, are yet to be determined. In this study, we examined in detail the effect of 2-Arachidonoylglycerol on the phagocytosis of opsonized zymosan by HL-60 cells that had differentiated into macrophage-like cells. We found that the addition of 2-Arachidonoylglycerol augmented the phagocytosis of opsonized zymosan by the differentiated HL-60 cells. The effect was observed from 1 nM and increased with increasing concentrations of 2-Arachidonoylglycerol. Treatment of the cells with SR144528 or pertussis toxin abolished the effect of 2-Arachidonoylglycerol, indicating that the CB2 receptor and Gi/o are involved in the augmented phagocytosis. Phosphatidylinositol 3-kinase and extracellular signal-regulated kinase were also suggested to be involved; treatment of the cells with wortmannin or PD98059 abrogated the 2-Arachidonoylglycerol-augmented phagocytosis. These results strongly suggest that 2-Arachidonoylglycerol, derived from stimulated inflammatory cells, has an important role in augmenting the phagocytosis of invading microorganisms by macrophages/monocytes thereby stimulating inflammatory reactions and immune responses.
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Synthesis and biological evaluation of several structural analogs of 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand.
Bioorganic & medicinal chemistry, 2006Co-Authors: Yoshitomo Suhara, Keizo Waku, Saori Oka, Hiroaki Takayama, Atsushi Kittaka, Takayuki SugiuraAbstract:2-Arachidonoylglycerol (2-AG (1)) is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). There is growing evidence that 2-Arachidonoylglycerol plays important physiological and pathophysiological roles in various mammalian tissues and cells, though the details remain to be clarified. In this study, we synthesized several remarkable analogs of 2-Arachidonoylglycerol, closely related in chemical structure to 2-Arachidonoylglycerol: an analog containing an isomer of arachidonic acid with migrated olefins (2-AGA118 (3)), an analog containing a one-carbon shortened fatty acyl moiety (2-AGA113 (4)), an analog containing an one-carbon elongated fatty acyl moiety (2-AGA114 (5)), a hydroxy group-containing analog (2-AGA105 (6)), a ketone group-containing analog (2-AGA109 (7)), and a methylene-linked analog (2-AGA104 (8)). We evaluated their biological activities as cannabinoid receptor agonists using NG108-15 cells which express the CB1 receptor and HL-60 cells which express the CB2 receptor. Notably, these structural analogs of 2-Arachidonoylglycerol exhibited only weak agonistic activities toward either the CB1 receptor or the CB2 receptor, which is in good contrast to 2-Arachidonoylglycerol which acted as a full agonist at these cannabinoid receptors. These results clearly indicate that the structure of 2-Arachidonoylglycerol is strictly recognized by the cannabinoid receptors (CB1 and CB2) and provide further evidence that the cannabinoid receptors are primarily the intrinsic receptors for 2-Arachidonoylglycerol.
Keizo Waku – One of the best experts on this subject based on the ideXlab platform.
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Synthesis and biological evaluation of several structural analogs of 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand.
Bioorganic & medicinal chemistry, 2006Co-Authors: Yoshitomo Suhara, Keizo Waku, Saori Oka, Hiroaki Takayama, Atsushi Kittaka, Takayuki SugiuraAbstract:2-Arachidonoylglycerol (2-AG (1)) is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). There is growing evidence that 2-Arachidonoylglycerol plays important physiological and pathophysiological roles in various mammalian tissues and cells, though the details remain to be clarified. In this study, we synthesized several remarkable analogs of 2-Arachidonoylglycerol, closely related in chemical structure to 2-Arachidonoylglycerol: an analog containing an isomer of arachidonic acid with migrated olefins (2-AGA118 (3)), an analog containing a one-carbon shortened fatty acyl moiety (2-AGA113 (4)), an analog containing an one-carbon elongated fatty acyl moiety (2-AGA114 (5)), a hydroxy group-containing analog (2-AGA105 (6)), a ketone group-containing analog (2-AGA109 (7)), and a methylene-linked analog (2-AGA104 (8)). We evaluated their biological activities as cannabinoid receptor agonists using NG108-15 cells which express the CB1 receptor and HL-60 cells which express the CB2 receptor. Notably, these structural analogs of 2-Arachidonoylglycerol exhibited only weak agonistic activities toward either the CB1 receptor or the CB2 receptor, which is in good contrast to 2-Arachidonoylglycerol which acted as a full agonist at these cannabinoid receptors. These results clearly indicate that the structure of 2-Arachidonoylglycerol is strictly recognized by the cannabinoid receptors (CB1 and CB2) and provide further evidence that the cannabinoid receptors are primarily the intrinsic receptors for 2-Arachidonoylglycerol.
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Evidence for the Involvement of the Cannabinoid CB2 Receptor and Its Endogenous Ligand 2-Arachidonoylglycerol in 12-O-Tetradecanoylphorbol-13-acetate-induced Acute Inflammation in Mouse Ear
The Journal of biological chemistry, 2005Co-Authors: Saori Oka, Keizo Waku, Maiko Gokoh, Seishi Kishimoto, Yoshio Ishima, Shin Yanagimoto, Shinobu Ikeda, Takayuki SugiuraAbstract:2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors. Two types of cannabinoid receptors have been identified to date. The CB1 receptor is abundantly expressed in the brain, and assumed to be involved in the attenuation of neurotransmission. On the other hand, the physiological roles of the CB2 receptor, mainly expressed in several types of inflammatory cells and immunocompetent cells, have not yet been fully elucidated. In this study, we investigated possible pathophysiological roles of the CB2 receptor and 2-Arachidonoylglycerol in acute inflinflammation in mouse ear induced by the topical application of 12-O-tetradecanoylphorbol-13-acetate. We found that the amount of 2-Arachidonoylglycerol was markedly augmented in inflamed mouse ear. In contrast, the amount of anandamide, another endogenous cannabinoid receptor ligand, did not change markedly. Importantly, 12-O-tetradecanoylphorbol-13-acetate-induced ear swelling was blocked by treatment with SR144528, a CB2 receptor antagonist, suggesting that the CB2 receptor is involved in the swelling. On the other hand, the application of AM251, a CB1 receptor antagonist, exerted only a weak suppressive effect. The application of SR144528 also reduced the 12-O-tetradecanoylphorbol-13-acetate-induced production of leukotriene B4 and the infiltration of neutrophils in the mouse ear. Interestingly, the application of 2-Arachidonoylglycerol to the mouse ear evoked swelling, which was abolished by treatment with SR144528. Nitric oxide was suggested to be involved in the ear swelling induced by 2-Arachidonoylglycerol. These results suggest that the CB2 receptor and 2-Arachidonoylglycerol play crucial stimulative roles during the course of inflammatory reactions.
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New perspectives in the studies on endocannabinoid and cannabis: 2-Arachidonoylglycerol as a possible novel mediator of inflammation.
Journal of pharmacological sciences, 2004Co-Authors: Takayuki Sugiura, Saori Oka, Maiko Gokoh, Seishi Kishimoto, Keizo WakuAbstract:2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors. To date, two types of cannabinoid receptors (CB1 and CB2) have been identified. The CB1 receptor is assumed to be involved in the attenuation of synaptic transmission. On the other hand, the physiological roles of the CB2 receptor, which is abundantly expressed in several types of inflammatory cells and immunocompetent cells, have not yet been fully elucidated. Recently, we investigated in detail possible physiological roles of the CB2 receptor and 2-Arachidonoylglycerol in inflammation. We found that 2-Arachidonoylglycerol induces the activation of p42/44 and p38 mitogen-activated protein kinases and c-Jun N-terminal kinase; actin rearrangement and morphological changes; augmented production of chemokines in HL-60 cells; and the migration of HL-60 cells differentiated into macrophage-like cells, human monocytes, natural killer cells, and eosinophils. We also found that the level of 2-Arachidonoylglycerol in mouse ear is markedly elevated following treatment with 12-O-tetradecanoylphorbol 13-acetate, which induces acute inflinflammation. Notably, the inflammation induced by 12-O-tetradecanoylphorbol 13-acetate was blocked by treatment with SR144528, a CB2-receptor antagonist. Similar results were obtained with an allergic inflinflammation model in mice. These results strongly suggest that 2-Arachidonoylglycerol plays essential roles in the stimulation of various inflammatory reactions in vivo.
Seishi Kishimoto – One of the best experts on this subject based on the ideXlab platform.
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2-Arachidonoylglycerol Enhances the Phagocytosis of Opsonized Zymosan by HL-60 Cells Differentiated into Macrophage-Like Cells
Biological & pharmaceutical bulletin, 2007Co-Authors: Maiko Gokoh, Saori Oka, Seishi Kishimoto, Takayuki SugiuraAbstract:2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). While evidence is accumulating that the CB1 receptor plays important regulatory roles in various nervous tissues and cells, the physiological roles of the CB2 receptor, which is abundantly expressed in the immune system, are yet to be determined. In this study, we examined in detail the effect of 2-Arachidonoylglycerol on the phagocytosis of opsonized zymosan by HL-60 cells that had differentiated into macrophage-like cells. We found that the addition of 2-Arachidonoylglycerol augmented the phagocytosis of opsonized zymosan by the differentiated HL-60 cells. The effect was observed from 1 nM and increased with increasing concentrations of 2-Arachidonoylglycerol. Treatment of the cells with SR144528 or pertussis toxin abolished the effect of 2-Arachidonoylglycerol, indicating that the CB2 receptor and Gi/o are involved in the augmented phagocytosis. Phosphatidylinositol 3-kinase and extracellular signal-regulated kinase were also suggested to be involved; treatment of the cells with wortmannin or PD98059 abrogated the 2-Arachidonoylglycerol-augmented phagocytosis. These results strongly suggest that 2-Arachidonoylglycerol, derived from stimulated inflammatory cells, has an important role in augmenting the phagocytosis of invading microorganisms by macrophages/monocytes thereby stimulating inflammatory reactions and immune responses.
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Chemotaxis of human peripheral blood eosinophils to 2-Arachidonoylglycerol: comparison with other eosinophil chemoattractants.
International Archives of Allergy and Immunology, 2006Co-Authors: Seishi Kishimoto, Maiko Gokoh, Saori Oka, Takayuki SugiuraAbstract:Background: 2-Arachidonoylglycerol (2-AG), an endogenous ligand for the cannabinoid receptors (CB1 and CB2), has been shown to exhibit a variety of cannabimimetic activities in vitr
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Suppression by WIN55212-2, a cannabinoid receptor agonist, of inflammatory reactions in mouse ear: Interference with the actions of an endogenous ligand, 2-Arachidonoylglycerol.
European journal of pharmacology, 2006Co-Authors: Saori Oka, Junichi Wakui, Maiko Gokoh, Seishi Kishimoto, Takayuki SugiuraAbstract:The effect of WIN55212-2, a cannabinoid receptor agonagonist, on acute inflinflammation of mouse ear was investigated. We found that topical application of WIN55212-2 suppressed ear swelling induced by 12-O-tetradecanoylphorbol 13-acetate or 2-Arachidonoylglycerol. Similar inhibition was observed with CP55940, another cannabinoid receptor agonagonist, and HU-308, a cannabinoid CB(2) receptor-selective agonist. WIN55212-2 also suppressed the infiltration of leukocytes induced by 12-O-tetradecanoylphorbol 13-acetate. On the other hand, WIN55212-3, an inactive enantiomer of WIN55212-2, exerted only small effects on inflammation. Notably, SR144528, a cannabinoid CB(2) receptor antagonist, also suppressed inflammatory reactions in mouse ear. Thus, both the cannabinoid CB(2) receptor agonist and antagonist are capable of reducing inflammatory reactions. We then investigated the mechanism underlying WIN55212-2-induced suppression of inflammation using cultured cells. We found that the addition of WIN55212-2 together with 2-Arachidonoylglycerol blocked 2-Arachidonoylglycerol-induced migration of human promyelocytic leukemia HL-60 cells that had been differentiated into macrophage-like cells. The restoration of 2-Arachidonoylglycerol-desensitized cells and WIN55212-2-desensitized cells from an anergic condition was examined next. We found that 2-Arachidonoylglycerol-treated cells rapidly recovered the capacity to respond to 2-Arachidonoylglycerol. On the other hand, the anergic condition toward 2-Arachidonoylglycerol continued for a longer period after pretreatment with WIN55212-2. These results suggest that the anti-inflammatory activity of WIN55212-2 is attributable, at least in part, to interference with the actions of the endogenous ligand, 2-Arachidonoylglycerol.
Sachiko Kondo – One of the best experts on this subject based on the ideXlab platform.
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Generation of 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, in picrotoxinin-administered rat brain.
Biochemical and biophysical research communications, 2000Co-Authors: Takayuki Sugiura, Sachiko Kondo, Keizo Waku, Naoki Yoshinaga, Yoshio IshimaAbstract:Abstract The levels of 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, and other molecular species of monoacylglycerols in rat brain were examined. In this study, we sacrificed the animals in liquid nitrogen to minimize postmortem changes. We found that rat brain contains 0.23 nmol/g tissue of 2-Arachidonoylglycerol, which accounts for 10.5% of the total monoacylglycerol present in this tissue. We next investigated the level of 2-Arachidonoylglycerol after in vivo stimulation with picrotoxinin. We found that the level of 2-Arachidonoylglycerol was elevated markedly in picrotoxinin-administered rat brain (4- to 6-fold over the control level). Changes in the levels of other molecular species were relatively small or negligible. Several cannabimimetic molecules as well as Δ 9 -tetrahydrocannabinol are known to depress neurotransmission and to exert anticonvulsant activities; endogenous 2-Arachidonoylglycerol produced during neural excitation may play a regulatory role in calming the enhanced synaptic transmission.
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evidence that 2 arachidonoylglycerol but not n palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid cb2 receptor comparison of the agonistic activities of various cannabinoid receptor ligands in hl 60 cells
Journal of Biological Chemistry, 2000Co-Authors: Takayuki Sugiura, Sachiko Kondo, Shinji Nakane, Tomoko Kodaka, Seishi Kishimoto, Tomoyuki Miyashita, Yoshitomo Suhara, Hiroaki Takayama, Keizo WakuAbstract:Abstract We examined the effect of 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, on the intracellular free Ca2+ concentrations in HL-60 cells that express the cannabinoid CB2 receptor. We found that 2-Arachidonoylglycerol induces a rapid transient increase in intracellular free Ca2+concentrations in HL-60 cells. The response was affected by neither cyclooxygenase inhibitors nor lipoxygenase inhibitors, suggesting that arachidonic acid metabolites are not involved. Consistent with this notion, free arachidonic acid was devoid of any agonistic activity. Importantly, the Ca2+ transient induced by 2-Arachidonoylglycerol was blocked by pretreatment of the cells with SR144528, a CB2 receptor-specific antagonist, but not with SR141716A, a CB1 receptor-specific antagonist, indicating the involvement of the CB2 receptor but not the CB1 receptor in this cellular response. Gi or Go is also assumed to be involved, because pertussis toxin treatment of the cells abolished the response. We further examined the structure-activity relationship. We found that 2-Arachidonoylglycerol is the most potent compound among a number of naturally occurring cannabimimetic molecules. Interestingly, anandamide and N-palmitoylethanolamine, other putative endogenous ligands, were found to be a weak partial agonagonist and an inactive ligand, respectively. These results strongly suggest that the CB2 receptor is originally a 2-Arachidonoylglycerol receptor, and 2-Arachidonoylglycerol is the intrinsic natural ligand for the CB2 receptor that is abundant in the immune system.
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Evidence That the Cannabinoid CB1 Receptor Is a 2-Arachidonoylglycerol Receptor STRUCTURE-ACTIVITY RELATIONSHIP OF 2-Arachidonoylglycerol, ETHER-LINKED ANALOGUES, AND RELATED COMPOUNDS
The Journal of biological chemistry, 1999Co-Authors: Takayuki Sugiura, Sachiko Kondo, Shinji Nakane, Tomoko Kodaka, Keizo Waku, Tomoyuki Miyashita, Yoshitomo Suhara, Hiroaki Takayama, Chiyo Seki, Naomichi BabaAbstract:Abstract An endogenous cannabimimetic molecule, 2-Arachidonoylglycerol, induces a rapid, transient increase in intracellular free Ca2+ concentrations in NG108–15 cells through a cannabinoid CB1 receptor-dependent mechanism. We examined the activities of 24 relevant compounds (2-Arachidonoylglycerol, its structural analogues, and several synthetic cannabinoids). We found that 2-Arachidonoylglycerol is the most potent compound examined so far: its activity was detectable from as low as 0.3 nm, and the maximal response induced by 2-Arachidonoylglycerol exceeded the responses induced by others. Activities of HU-210 and CP55940, potent cannabinoid receptor agonists, were also detectable from as low as 0.3 nm, whereas the maximal responses induced by these compounds were low compared with 2-Arachidonoylglycerol. Anandamide was also found to act as a partial agonagonist in this assay system. We confirmed that free arachidonic acid failed to elicit a response. Furthermore, we found that a metabolically stable ether-linked analogue of 2-Arachidonoylglycerol possesses appreciable agonistic activity, although its activity was apparently lower than that of 2-Arachidonoylglycerol. We also confirmed that pretreating cells with various cannabinoid receptor agonists nullified the response induced by 2-Arachidonoylglycerol, whereas pretreating cells with other neurotransmitters or neuromodulators did not affect the response. These results strongly suggested that the cannabinoid CB1 receptor is originally a 2-Arachidonoylglycerol receptor, and 2-Arachidonoylglycerol is the intrinsic physiological ligand for the cannabinoid CB1 receptor.
Shinji Nakane – One of the best experts on this subject based on the ideXlab platform.
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Synthesis and biological activities of novel structural analogues of 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand.
Bioorganic & medicinal chemistry letters, 2001Co-Authors: Yoshitomo Suhara, Shinji Nakane, Keizo Waku, Yoshio Ishima, Hiroaki Takayama, Shunsuke Arai, Takayuki SugiuraAbstract:Novel analogues of 2-Arachidonoylglycerol (2-AG), an endogenous cannabinoid receptor ligand, were developed. Chemical synthesis of these analogues (2-AGA105 and 2-AGA109) was accomplished starting from 2-octyn-1-ol and diethyl malomalonate and employing Wittig coupling of triene phosphonate with an aldehyde intermediate in a convergent and stereoselective manner. These analogues should be useful lead compounds for the development of novel 2-AG mimetics.
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evidence that 2 arachidonoylglycerol but not n palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid cb2 receptor comparison of the agonistic activities of various cannabinoid receptor ligands in hl 60 cells
Journal of Biological Chemistry, 2000Co-Authors: Takayuki Sugiura, Sachiko Kondo, Shinji Nakane, Tomoko Kodaka, Seishi Kishimoto, Tomoyuki Miyashita, Yoshitomo Suhara, Hiroaki Takayama, Keizo WakuAbstract:Abstract We examined the effect of 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, on the intracellular free Ca2+ concentrations in HL-60 cells that express the cannabinoid CB2 receptor. We found that 2-Arachidonoylglycerol induces a rapid transient increase in intracellular free Ca2+concentrations in HL-60 cells. The response was affected by neither cyclooxygenase inhibitors nor lipoxygenase inhibitors, suggesting that arachidonic acid metabolites are not involved. Consistent with this notion, free arachidonic acid was devoid of any agonistic activity. Importantly, the Ca2+ transient induced by 2-Arachidonoylglycerol was blocked by pretreatment of the cells with SR144528, a CB2 receptor-specific antagonist, but not with SR141716A, a CB1 receptor-specific antagonist, indicating the involvement of the CB2 receptor but not the CB1 receptor in this cellular response. Gi or Go is also assumed to be involved, because pertussis toxin treatment of the cells abolished the response. We further examined the structure-activity relationship. We found that 2-Arachidonoylglycerol is the most potent compound among a number of naturally occurring cannabimimetic molecules. Interestingly, anandamide and N-palmitoylethanolamine, other putative endogenous ligands, were found to be a weak partial agonist and an inactive ligand, respectively. These results strongly suggest that the CB2 receptor is originally a 2-Arachidonoylglycerol receptor, and 2-Arachidonoylglycerol is the intrinsic natural ligand for the CB2 receptor that is abundant in the immune system.
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Synthesis and biological activities of 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, and its metabolically stable ether-linked analogues.
Chemical & pharmaceutical bulletin, 2000Co-Authors: Yoshitomo Suhara, Shinji Nakane, Keizo Waku, Tomoyuki Miyashita, Hiroaki Takayama, Takayuki SugiuraAbstract: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 boraborate. 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 agonagonist. Compounds 4 and 5 would also be valuable as control molecules in experiments where 2 is employed.