Formation of N-Acyl-phosphatidylethanolamines and N-Acylethanolamines

Hansen, Harald S.; Lauritzen, Lotte; Moesgaard, Birthe; Strand, Anne Mette; Hansen, Henrik H.

doi:10.1016/s0006-2952(97)00396-1

Cited by 87 publications

(76 citation statements)

References 86 publications

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“…The endocannabinoid AEA is thought to exert antiin¯ammatory and neuroprotective actions (Di Marzo et al, 2000a;Hansen et al, 1998). As it was found to inhibit the reuptake and hydrolysis of AEA in vitro (Rakhshan et al, 2000;Watanabe et al, 1996), it is possible that CBD acts in part by interfering with AEA inactivation, thereby enhancing the putative tonic inhibitory action of AEA on in¯ammation.…”

Section: Discussionmentioning

confidence: 99%

“…It was found that CBD inhibits both AEA hydrolysis by FAAH-containing membrane preparations (Watanabe et al, 1996), and AEA uptake by RBL ± 2H3 cells via the AMT (Rakhshan et al, 2000). Although these e ects were observed at high mM concentrations, these ®ndings raised the possibility that some of the pharmacological actions of CBD might be due to inhibition of AEA degradation, with subsequent enhancement of the endogenous levels of this mediator, for which neuroprotective (Hansen et al, 1998) and antiin¯ammatory (Di Marzo et al, 2000a) properties have been previously suggested.…”

Section: Introductionmentioning

confidence: 94%

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Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide

Bisogno¹,

Hanŭs

Petrocellis

et al. 2001

British J Pharmacology

1,167

817

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1 (7)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-in¯ammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). 2 CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5' pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca 2+ concentrations in cells over-expressing human VR1; (b) [ 14 C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [ 14 C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase. 3 Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC 50 =3.2 ± 3.5 mM, and with a maximal e ect similar in e cacy to that of capsaicin, i.e. 67 ± 70% of the e ect obtained with ionomycin (4 mM). CBD (10 mM) desensitized VR1 to the action of capsaicin. The e ects of maximal doses of the two compounds were not additive. 4 (+)-5'-DMH-CBD and (+)-7-hydroxy-5'-DMH-CBD inhibited [ 14 C]-AEA uptake (IC 50 =10.0 and 7.0 mM); the (7)-enantiomers were slightly less active (IC 50 =14.0 and 12.5 mM). CBD and (+)-CBD were also active (IC 50 =22.0 and 17.0 mM). 5 CBD (IC 50 =27.5 mM), (+)-CBD (IC 50 =63.5 mM) and (7)-7-hydroxy-CBD (IC 50 =34 mM), but not the other analogues (IC 50 4100 mM), weakly inhibited [ 14 C]-AEA hydrolysis. 6 Only the (+)-isomers exhibited high a nity for CB 1 and/or CB 2 cannabinoid receptors. 7 These ®ndings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological e ects of CBD and its analogues. In view of the facile high yield synthesis, and the weak a nity for CB 1 and CB 2 receptors, (7)-5'-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide

Bisogno¹,

Hanŭs

Petrocellis

et al. 2001

British J Pharmacology

1,167

817

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“…Both endocannabinoids are produced at post-synaptic neurons. For anandamide, the main biosynthetic pathway consists of a two-step process: (1) formation of N-acylphosphatidyl-ethanolamine (NAPE) from phosphatidylethanolamine by a calcium-dependent N-acyltransferase, and (2) hydrolysis of NAPE to form N-acylethanolamines in a process that is catalysed by NAPE-hydrolysing phospholipase D (38)(39)(40) (Fig. 1).…”

Section: Endocannabinoids Biosynthesis and Uptakementioning

confidence: 99%

PUFA-derived endocannabinoids: an overview

Cascio

2013

Proc. Nutr. Soc.

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Following on from the discovery of cannabinoid receptors, of their endogenous agonists (endocannabinoids) and of the biosynthetic and metabolic enzymes of the endocannabinoids, significant progress has been made towards the understanding of the role of the endocannabinoid system in both physiological and pathological conditions. Endocannabinoids are mainly n-6 long-chain PUFA (LCPUFA) derivatives that are synthesised by neuronal cells and inactivated via a two-step process that begins with their transport from the extracellular to the intracellular space and culminates in their intracellular degradation by hydrolysis or oxidation. Although the enzymes responsible for the biosynthesis and metabolism of endocannabinoids have been well characterised, the processes involved in their cellular uptake are still a subject of debate. Moreover, little is yet known about the roles of endocannabinoids derived from n-3 LCPUFA such as EPA and DHA. Here, I provide an overview of what is currently known about the mechanisms for the biosynthesis and inactivation of endocannabinoids, together with a brief analysis of the involvement of the endocannabinoids in both food intake and obesity. Owing to limited space, recent reviews will be often cited instead of original papers.

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“…However, we (6, 7) and others (8 -11) have found that the levels of anandamide are very low in several mammalian tissues. In addition, the biosynthetic pathways for anandamide, either the N-acylphosphatidylethanolamine pathway (6,7,(11)(12)(13)(14) or the condensation pathway (7,(15)(16)(17)(18), do not appear able to provide large amounts of anandamide, at least under normal conditions in living tissues, because the availabilities of the substrates are very low. Furthermore, several investigators demonstrated that anandamide is produced mainly in the post-mortem period in the brain (8,10).…”

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confidence: 99%

Evidence That the Cannabinoid CB1 Receptor Is a 2-Arachidonoylglycerol Receptor

Sugiura¹,

Kodaka²,

Nakane³

et al. 1999

Journal of Biological Chemistry

299

106

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An endogenous cannabimimetic molecule, 2-arachidonoylglycerol, induces a rapid, transient increase in intracellular free Ca 2؉ 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 agonist 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.It is well known that ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC), 1 a psychoactive ingredient of marijuana, possesses a variety of pharmacological activities in vitro and in vivo (1), although, until recently, the mechanism of the action of ⌬ 9 -THC had long been unelucidated. In 1988, Devane et al. (2) provided evidence that a specific binding site(s) for cannabinoids is present in the brain. Soon after, Matsuda et al. (3) cloned a cDNA encoding a cannabinoid receptor (CB1) from a rat brain cDNA library. These findings raised the possibility that at least part of the action of ⌬ 9 -THC is mediated through such a specific receptor and prompted the search for endogenous cannabinoid receptor ligands in mammalian tissues.In 1992, Devane et al. (4) isolated N-arachidonoylethanolamine (anandamide) from porcine brain as the first endogenous cannabinoid receptor ligand. They demonstrated that anandamide exhibits several cannabimimetic activities in vitro and in vivo (4, 5). So far, a number of studies have been carried out on anandamide, and it has been assumed that anandamide is one of the important lipid mediators in the nervous system as well as in other systems (5). However, we (6, 7) and others (8 -11) have found that the levels of anandamide are very low in several mammalian tissues. In addition, the biosynthetic pathways for anandamide, either the N-acylphosphatidylethanolamine pathway (6,7,(11)(12)(13)(14) or t...

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Formation of N-Acyl-phosphatidylethanolamines and N-Acylethanolamines

Cited by 87 publications

References 86 publications

Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide

Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide

PUFA-derived endocannabinoids: an overview

Evidence That the Cannabinoid CB1 Receptor Is a 2-Arachidonoylglycerol Receptor

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