Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P21554 (cannabinoid receptor)
3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of rat hepatocytes with anandamide (arachidonoylethanolamide) inhibited acetyl-CoA carboxylase activity and fatty acid synthesis de novo without affecting fatty acid synthase. This was concomitant to a decrease in the intracellular levels of malonyl-CoA. Likewise, anandamide depressed both cholesterol synthesis de novo and the incorporation of exogenous palmitate into triacylglycerols and phospholipids. On the other hand, anandamide stimulated in parallel both carnitine palmitoyltransferase I activity and ketogenesis from palmitate, though ketogenesis from octanoate was unaffected. The effects of anandamide on hepatic fatty acid synthesis and oxidation were: (a) mimicked by arachidonic acid, a product of anandamide breakdown by anandamide amidase; (b) prevented by phenylmethylsulfonyl fluoride, an inhibitor of anandamide amidase; and (c) not affected by bisindolylmaleimide, a specific inhibitor of protein kinase C. Furthermore, delta 9-tetrahydrocannabinol had no effect on any of the parameters determined, ruling out the possibility that the effects of anandamide on hepatic fatty acid metabolism are mediated by the peripheral cannabinoid receptor. The results thus indicate that anandamide might function as a carrier of arachidonic acid in the modulation of hepatic fatty metabolism.
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PMID:Effects of anandamide on hepatic fatty acid metabolism. 757 52

The endogenous cannabinoid receptor ligand, anandamide, produced a concentration related inhibition of electrically evoked contractions of the guinea-pig myenteric plexus preparation. Its potency was markedly enhanced by phenylmethylsulphonyl fluoride (2.0-200 microM) which presumably acts by inhibiting the hydrolysis of anandamide in this preparation. The degree of this potentiation increased with the concentration of phenylmethylsulphonyl fluoride used. The methyl analogue of anandamide, R-(+)-arachidonyl-1'-hydroxy-2'-propylamide, also inhibited contractions of the guinea-pig myenteric plexus preparation. The potency of this compound was much less affected by phenylmethylsulphonyl fluoride than was the potency of anandamide, confirming its greater resistance to hydrolysis. Phenylmethylsulphonyl fluoride did not alter the inhibitory potency of the cannabinoid, CP 55,940 ((-)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4- [3-hydroxypropyl]cyclohexan-1-ol), which is not an amidase substrate. Nor did phenylmethylsulphonyl fluoride affect the ability of anandamide to inhibit electrically evoked contractions of the mouse vas deferens, suggesting that anandamide does not undergo hydrolysis in this tissue.
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PMID:Effect of phenylmethylsulphonyl fluoride on the potency of anandamide as an inhibitor of electrically evoked contractions in two isolated tissue preparations. 771 52

Arachidonylethanolamide (N-2-hydroxyethyl-arachidonamide) or 'anandamide' is a naturally occurring derivative of arachidonic acid that has been shown to bind and activate cannabinoid receptors in the brain. Since other potent ligands for the cannabinoid receptor have an aromatic hydroxyl group, we investigated the hypothesis that replacement of the ethanolamine hydroxyl with an aromatic hydroxyl will increase the binding affinity for the cannabinoid receptor. Two novel congeners of anandamide containing aromatic hydroxyl groups were synthesized: N-2-(4-hydroxyphenyl)ethyl arachidonamide (HEA) and N-2-hydroxyphenyl arachidonamide (HPA). The affinity of these congeners for the brain cannabinoid receptor was determined by competition with [3H]CP55940. HEA competed for [3H]CP55940 binding with a Ki of 600 nM; HPA had a Ki of 2200 nM. These results indicate that increased size in the amide portion of anandamide decreases affinity for the receptor. Phenylmethylsulfonyl fluoride (PMSF), an inhibitor of anandamide catabolism by brain membranes, had no effect on the binding of either HEA or HPA. We conclude that these congeners are not substrates for the amidase that catabolizes anandamide.
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PMID:The binding of novel phenolic derivatives of anandamide to brain cannabinoid receptors. 778 62

Arachidonoyl ethanolamide (anandamide) is a naturally occurring brain constituent that binds to a specific brain cannabinoid receptor (CBR1). An amidase activity (anandamide amidase) in membrane fractions of brain and in cultured neuroblastoma cells rapidly degrades anandamide to arachidonic acid (Deutsch, D. G., and Chin, S. (1993) Biochem. Pharmacol. 46, 791-796). In the current study, analogs of anandamide representing three classes of putative transition-state inhibitor (trifluoromethyl ketones, alpha-keto esters, and alpha-keto amides) were synthesized and tested as inhibitors of anandamide hydrolysis in vitro and as ligands for CBR1. The trifluoromethyl ketones and alpha-keto esters showed nearly 100% inhibition of anandamide hydrolysis in vitro at 7.5 microM inhibitor and 27.7 microM anandamide. Arachidonyl trifluoromethyl ketone was the only synthetic compound in the series of fatty acid derivatives able to displace [3H]CP-55940 binding to CBR1 with a Ki of 0.65 microM. It was also the most effective inhibitor in intact neuroblastoma cells, leading to a 12-fold increase of cellular anandamide levels at 12 microM. From the action of these inhibitors on this hydrolytic enzyme, it seems likely that anandamide is cleaved by a mechanism that involves an active-site serine hydroxyl group. These inhibitors may serve as useful tools to elucidate the role anandamide plays in vivo.
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PMID:Inhibitors of arachidonoyl ethanolamide hydrolysis. 808 91

The purpose of this study was to investigate whether anandamide induces cannabimimetic responses, mainly mobilization of arachidonic acid, in primary cultures of rat brain cortical astrocytes. Confluent monolayer cultures of astrocytes, prelabeled with [3H]arachidonic acid, were incubated with anandamide or delta9-tetrahydrocannabinol (delta9-THC) in the presence or absence of thimerosal, a fatty acid acyl CoA transferase inhibitor and phenylmethylsulfonyl fluoride, an amidohydrolase inhibitor. Anandamide and delta9-THC induced a time- and concentration-dependent release of arachidonic acid in the presence, but not in the absence, of thimerosal. Anandamide- and delta9-THC-stimulated arachidonic acid release was pertussis toxin-sensitive, indicating a receptor/G-protein involvement. A novel and selective cannabinoid receptor antagonist, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboximide hydrochloride], blocked the arachidonic acid release, suggesting a cannabinoid receptor-mediated pathway. In astrocytes, the magnitude of anandamide-induced arachidonic acid release was equal to that released by equimolar concentrations of delta9-THC. Furthermore, direct assay of amidohydrolase activity indicated that degradation of anandamide into arachidonic acid and ethanolamine was negligible in cortical astrocytes. Our results suggest that anandamide stimulates receptor-mediated release of arachidonic acid, and the receptor may be the cannabinoid receptor. Astrocytes, containing a cannabinoid receptor and lower or negligible amidohydrolase activity, may be an important brain cell model in which to study the cannabimimetic effects of anandamide at a cellular and molecular level.
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PMID:Anandamide- and delta9-tetrahydrocannabinol-evoked arachidonic acid mobilization and blockade by SR141716A [N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4 -methyl-1H-pyrazole-3-carboximide hydrochloride]. 861 4

Long-chain N-acylethanolamines (NAEs) elicit a variety of biological and pharmacological effects. Anandamide (20:4n-6 NAE) and other polyunsaturated NAEs bind to the cannabinoid receptor and may thus serve as highly specific lipid mediators of cell signalling. NAEs can be formed by phospholipase D-catalyzed hydrolysis of N-acylethanolamine phospholipids or by direct condensation of ethanolamine and fatty acid. So far, most of the latter biosynthetic activity has been shown to be the reverse reaction of the NAE amidohydrolase that catalyzes NAE degradation. Thus, increasing evidence supports the hypothesis that the N-acylation-phosphodiesterase pathway yields not only saturated-monounsaturated NAEs, but polyunsaturated ones, including anandamide, as well.
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PMID:The N-acylation-phosphodiesterase pathway and cell signalling. 868 24

Anandamide amidase (EC 3.5.1.4) is responsible for the hydrolysis of arachidonoyl ethanolamide (anandamide). Relatively selective and potent enzyme reversible inhibitors effective in the low micromolar range, such as arachidonyl trifluoromethyl ketone (Arach-CF3), have been described (Koutek et al., J Biol Chem 269: 22937-22940, 1994). In the current study, methyl arachidonyl fluorophosphonate (MAFP), an arachidonyl binding site directed phosphonylation reagent, was tested as an inhibitor of anandamide amidase and as a ligand for the CB1 cannabinoid receptor. MAFP was 800 times more potent than Arach-CF3 and phenylmethylsulfonyl fluoride (PMSF) as an amidase inhibitor in rat brain homogenates. In intact neuroblastoma cells, MAFP was also approximately 1000-fold more potent than Arach-CF3. MAFP demonstrated selectivity towards anandamide amidase for which it was approximately 3000 and 30,000-fold more potent than it was towards chymotrypsin and trypsin, respectively. MAFP displaced [3H]CP-55940 binding to the CB1 cannabinoid receptor with an IC50 of 20 nM vs 40 nM for anandamide. It bound irreversibly and prevented subsequent binding of the cannabinoid radioligand [3H]CP-55940 at that locus. These studies suggest that MAFP is a potent and specific inhibitor of anandamide amidase and, in addition, can interact with the cannabinoid receptors at the cannabinoid binding site. This is the first report of a potent and relatively selective irreversible inhibitor of arachidonoyl ethanolamide amidase.
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PMID:Methyl arachidonyl fluorophosphonate: a potent irreversible inhibitor of anandamide amidase. 906 28

The endogenous cannabinoid receptor agonist anandamide is present in central and peripheral tissues. As the kidney contains both the amidase that degrades anandamide and transcripts for anandamide receptors, we characterized the molecular components of the anandamide signaling system and the vascular effects of exogenous anandamide in the kidney. We show that anandamide is present in kidney homogenates, cultured renal endothelial cells (EC), and mesangial cells; these cells also contain anandamide amidase. Reverse-transcriptase PCR shows that EC contain transcripts for cannabinoid type 1 (CB1) receptors, while mesangial cells have mRNA for both CB1 and CB2 receptors. EC exhibit specific, high-affinity binding of anandamide (Kd = 27.4 nM). Anandamide (1 microM) vasodilates juxtamedullary afferent arterioles perfused in vitro; the vasodilation can be blocked by nitric oxide (NO) synthase inhibition with L-NAME (0.1 mM) or CB1 receptor antagonism with SR 141716A (1 microM), but not by indomethacin (10 microM). Anandamide (10 nM) stimulates CB1-receptor-mediated NO release from perfused renal arterial segments; a similar effect was seen in EC. Finally, anandamide (1 microM) produces a NO-mediated inhibition of KCl-stimulated [3H]norepinephrine release from sympathetic nerves on isolated renal arterial segments. Hence, an anandamide signaling system is present in the kidney, where it exerts significant vasorelaxant and neuromodulatory effects.
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PMID:Production and physiological actions of anandamide in the vasculature of the rat kidney. 929 22

We have investigated the biosynthesis of long-chain N-acylethanolamines (NAEs) from endogenous substrates in rat testes membranes with special emphasis on anandamide (20:4n-6 NAE), a cannabinoid receptor agonist. Incubation of various membrane preparations with 5 mM Ca2+ produced both N-acyl phosphatidylethanolamine (N-acyl PE) and NAE with primarily (approximately 85%) N-palmitoyl groups (16:0 NAE) and less than 2% 20:4n-6 NAE. In contrast, incubation of these membranes with 5 mM EGTA and 10 mM ethanolamine had little effect on N-acyl PE composition but yielded NAEs whose major constituent (32-37%) was anandamide. Incubations with [1,1,2,2,-2H4]ethanolamine in media containing 40% H2(18)O showed that the Ca(2+)-independent NAE synthesis occurred by direct condensation of ethanolamine with free fatty acids present in the membrane preparation. This biosynthetic activity occurred at ethanolamine concentrations as low as 50 microM and exhibited substrate selectivity for arachidonate which increased with increasing ethanolamine concentrations. The results of inhibitor experiments suggest that the Ca(2+)-independent NAE synthesis was catalyzed by the NAE amidohydrolase acting in reverse. This condensation reaction could be important in agonist-induced anandamide synthesis for cell signalling through cannabinoid receptors.
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PMID:Alternative pathways of anandamide biosynthesis in rat testes. 963 36

Arachidonylethanolamide (AEA), the putative endogenous ligand of the cannabinoid receptor, has been shown to be a substrate for lipoxygenase enzymes in vitro. One goal of this study was to determine whether lipoxygenase-rich cells metabolize AEA. [14C]AEA was converted by human polymorphonuclear leukocytes (PMNs) to two major metabolites that comigrated with synthetic 12(S)- and 15(S)-hydroxy-arachidonylethanolamide (HAEA). Human platelets convert [14C]AEA to 12(S)-HAEA. 12(S)-HAEA binds to both CB1 and CB2 receptors with approximately the same affinity as AEA. 12(R)-HAEA, which is not produced by PMNs, has 2-fold lower affinity for the CB1 receptor and 10-fold lower affinity for the CB2 receptor than 12(S)-HAEA. 15-HAEA has a lower affinity than AEA for both receptors, with Ki values of 738 and >1000 nM for CB1 and CB2 receptors, respectively. The addition of a hydroxyl group at C20 of AEA resulted in a ligand with the same affinity for the CB1 receptor but a 4-fold lower affinity for the CB2 receptor than AEA. 12(S)-HAEA and 15-HAEA are poor substrates for AEA amidohydrolase and do not bind to the AEA uptake carrier. In conclusion, the addition of a hydroxyl group at C12 of the arachidonate backbone of AEA does not affect binding to CB receptors but is likely to increase its half-life. The addition of hydroxyl groups at other positions affects ligand affinity for CB receptors; both the position of the hydroxyl group and the configuration of the remaining double bonds are determinants of affinity.
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PMID:Human platelets and polymorphonuclear leukocytes synthesize oxygenated derivatives of arachidonylethanolamide (anandamide): their affinities for cannabinoid receptors and pathways of inactivation. 965 4


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