111-58-0

Basic information

• Product Name: N-Oleoylethanolamine
• Synonyms: ODA;OLEIC ACID-2,6-DIISOPROPYL ANILIDE;N-[2,6-BIS(1-METHYLETHYL)PHENYL]-9Z-OCTADECENAMIDE;N-(2-hydroxyethyl)-,(Z)-9-Octadecenamide;Oleoylmonoethanolamide;OLEAMIDE MEA;9-Octadecenamide, N-(2-hydroxyethyl)-, (9Z)-;(Z)-N-(2-hydroxyethyl)octadec-9-enamide
• CAS NO: 111-58-0
• Molecular Formula: C₂₀H₃₉NO₂
• Molecular Weight: 325.53
• EINECS: 203-884-8
• Product Categories: Fluorobenzene;Intracellular receptor
• Mol File: 111-58-0.mol

Chemical Properties

• Melting Point: 63-64 °C
• Boiling Point: 496.35 °C at 760 mmHg
• Flash Point: 253.984 °C
• Appearance: /
• Density: 0.915 g/cm³
• Vapor Pressure: 6.22E-12mmHg at 25°C
• Refractive Index: 1.473
• Storage Temp.: −20°C
• Solubility: Soluble in DMSO (up to 25 mg/ml) or in Ethanol (up to 35 mg/ml)
• PKA: 14.49±0.10(Predicted)
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 1 month.
• CAS DataBase Reference: N-Oleoylethanolamine(CAS DataBase Reference)
• NIST Chemistry Reference: N-Oleoylethanolamine(111-58-0)
• EPA Substance Registry System: N-Oleoylethanolamine(111-58-0)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36
• WGK Germany: 2
• HazardClass: IRRITANT
• Hazardous Substances Data: 111-58-0(Hazardous Substances Data)

Usage

Uses

1. Used in Pharmaceutical Applications:
N-Oleoylethanolamine is used as a therapeutic agent for appetite regulation and weight management due to its PPARα-mediated mechanism. It suppresses food intake and reduces weight gain in rats and PPARα wild-type mice.
2. Used in Research Applications:
N-Oleoylethanolamine is used as a research tool to study its effects on glucagon-like peptide (GLP)-1RA-mediated anorectic signaling and weight loss.
3. Used in Gastrointestinal Applications:
N-Oleoylethanolamine is used as a signaling molecule in the gastrointestinal system, generating an intestinal signal that stimulates central dopamine activity, establishing a link between caloric-homeostatic and hedonic-homeostatic controllers.
4. Used in Obesity Treatment:
N-Oleoylethanolamine has been implicated as the molecular mechanism associated with gastric bypass success, potentially contributing to its use in the treatment of obesity.
5. Used in Endocannabinoid System Research:
As an analog of the endocannabinoid anandamide, N-Oleoylethanolamine is used in research to understand the endocannabinoid system's role in various physiological processes, including appetite regulation and energy balance.
6. Used in Neurological Applications:
N-Oleoylethanolamine, being produced in neurons and astrocytes, is used in research to explore its potential roles in neurological functions and the treatment of neurological disorders.
7. Used in Aging and Longevity Research:
N-Oleoylethanolamine is used as a geroprotector in aging and longevity research, investigating its potential to extend healthy lifespan and delay the onset of age-related diseases.
8. Used in Lipid Metabolism Research:
As an N-(long-chain-acyl)ethanolamine, N-Oleoylethanolamine is used in research to study its role in lipid metabolism and its potential applications in the treatment of metabolic disorders.

Biosynthesis

Oleoylethanolamide (OEA) is produced by the small intestine following feeding in two steps. First an N-acyl transferase (NAT) activity joins the free amino terminus of phosphatidylethanolamine (PE) to the oleoyl group (one variety of acyl group) derived from sn-1-oleoyl-phosphatidylcholine, which contains the fatty acid oleic acid at the sn-1 position. This produces an N-acylphosphatidylethanolamine, which is then split (hydrolyzed) by N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) into phosphatidic acid and OEA. The biosynthesis of OEA and other bioactive lipid amides is modulated by bile acids.

Biological Functions

N-Oleoyl Ethanolamide is also a predominant NAE species in the injured rat brain, and it has also been found to be the major NAE species in a human brain that has suffered a hemispheric stroke. As early as 1975, N-Oleoyl Ethanolamide was synthesized as an inhibitor of ceramidase, the enzyme that degrades ceramide. Ceramide is involved in the regulation of apoptosis and cell proliferation. Cannabinoid-induced apoptosis in glioma cells is mediated via formation of ceramide. On a tentative basis, it can be suggested that anandamide-induced apoptosis may be aggravated by the presence of N-Oleoyl Ethanolamide because this leads to increased formation of ceramide. There are numerous studies in which N-Oleoyl Ethanolamide has been shown to facilitate the apoptosis-inducing effect of different compounds mediated via increased ceramide levels. However, it has also been reported that N-Oleoyl Ethanolamide decreases ceramide levels in JB6 P+ cells by an unknown mechanism. Recently, N-Oleoyl Ethanolamide has been shown to have a CB1-receptor-independent anorexic effect by inhibiting some intestinal neuronal functions in the rat, and it also causes vasodilation in rat mesenteric arterial segments by an unknown receptor mechanism. Whether these recently discovered biological effects of N-Oleoyl Ethanolamide are of significance for neuroprotection is not known, but it indicates that nonendocannabinoid NAEs are also bioactive molecules with potential for cerebral actions.

Biological Activity

Lipid mediator and analog of anandamide (N-(2-Hydroxyethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide ) that is involved in peripheral regulation of feeding. Selective GPR55 agonist (EC 50 values are 0.44, >30 and >30 μ M at GPR55, CB 1 and CB 2 respectively) and PPAR α agonist (EC 50 = 120 nM). Induces satiety through activation of PPAR α and is also a ceramidase inhibitor. Also endogenous agonist at the GPR119 receptor.

Biochem/physiol Actions

Oleoylethanolamide (OEA) is a lipid mediator, which helps to control various biological functions, like food intake. It modulates the gene expression in the small intestine. OEA has the ability to initiate several receptors, such as cannabinoid receptor type 1 (CB1), peroxisome proliferator-activated receptors (PPARs) and G protein-coupled receptor 119 (GPR119).

Enzyme inhibitor

This endocannabinoid-related metabolite (N-Oleoyl Ethanolamide; FW = 325.54 g/mol; CAS 111- 58-0; Symbol: NOE and OEA; Soluble in Ethanol, Chloroform, or Methanol) is widely employed to inhibit acid and neutral ceramidases (IC50 ~ 500 μM) that cleave fatty acids from ceramide, producing sphingosine (SPH), which is then enzymatically phosphorylated to form the receptorsensed metabolite, sphingosine-1-phosphate, or S1P. NOE also inhibits the glucosylation of naturally occurring ceramides. In CHP-100 neuroepithelioma cells treated with N-hexanoylsphingosine (C6-Cer; 30 μM), NOE affected only marginally short-chain glucocerebroside accumulation, but markedly decreased accumulation of glucocerebrosides originating from glucosylation of a long-chain ceramide (Lc-Cer) produced upon C6-Cer treatment. NOE also inhibits fatty acid hydrolase (or FAAH), an integral membrane hydrolase possessing an unusual catalytic triad Ser-Ser-Lys.N-Oleoyl Ethanolamide is also an effective inhibitor of mitochondrial swelling, but does not inhibit phospholipase A2 or ruthenium red-induced Ca2+ release. Moreover, among naturally occurring Nacylethanolamines, only NOE (at 10 μM) inhibits the accumulation of Narachidonoylethanolamine (or Anandamide, AEA), a putative endogenous ligand of the cannabinoid receptor, into cerebellar granule cells occurs by means of facilitated diffusion.

References

1) Lo Verme et al. (2005), Regulation of food intake by oleoylethanolamide; Cell Mol. Life Sci. 62 7082) Magotti et al. (2015), Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids; Structure 23 5983) Overton et al. (2006), Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecules hypophagic agents; Cell Metab. 3 1674) Brown (2007), Novel cannabinoid receptors; Br. J. Pharmacol. 152 5675) Nielson et al. (2004), Food intake is inhibited by oral oleoylethanolamide; J. Lipid Res. 45 10276) Folick et al. (2015), Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans; Science 347 83

InChI:InChI=1/C20H39NO2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-20(23)21-18-19-22/h9-10,22H,2-8,11-19H2,1H3,(H,21,23)/b10-9-

Upstream product

• 112-80-1 cis-Octadecenoic acid 
• 141-43-5 ethanolamine 
• 112-77-6 (Z)-9-octadecenoyl chloride 
• 112-62-9 Methyl oleate 
• 60-33-3 linoleic acid 
• 1415264-52-6 O-oleoylethanolamide trifluoroacetate 

Downstream Products

• 24435-25-4 NAEPA 
• 6301-24-2 2-(8-heptadecenyl)-2-oxazoline 
• 2601-90-3 N-[(9Z)-1-oxo-9-octadecenyl]glycine 
• 183323-44-6 Phosphoric acid dibenzyl ester 2-((Z)-octadec-9-enoylamino)-ethyl ester 

Related news

Design, synthesis and activity as acid ceramidase inhibitors of 2-oxooctanoyl and N-Oleoylethanolamine (cas 111-58-0) analogues08/22/2019

The synthesis of novel N-acylethanolamines and their use as inhibitors of the aCDase is reported here. The compounds are either 2-oxooctanamides or oleamides of sphingosine analogs featuring a 3-hydroxy-4,5-hexadecenyl tail replaced by ether or thioether moieties. It appears that, within the 2-o...detailed

Cardiovascular PharmacologyHydrogen peroxide as a mediator of vasorelaxation evoked by N-Oleoylethanolamine (cas 111-58-0) and anandamide in rat small mesenteric arteries08/21/2019

Hydrogen peroxide (H2O2) has been shown to participate in endothelium-derived hyperpolarising factor (EDHF)-mediated mechanisms. Vasorelaxation to the endocannabinoid-like N-oleoylethanolamine (OEA) and anandamide has been shown to be endothelium-dependent. Therefore, the principal aim was to in...detailed

Relevant articles and documents

Selective synthesis of unsaturated N-acylethanolamines by lipase-catalyzed N-acylation of ethanolamine with unsaturated fatty acids

The selective synthesis of unsaturated N-acylethanolamines 1b-6b by lipase-catalyzed direct condensation between unsaturated fatty acids 1a-6a and ethanolamine is reported. Reactions were carried out in hexane at 40 °C, in the presence of Candida antarctica Lipase B as the catalyst, to give the corresponding amides 1b-6b with yields ranging from 80 to 88%.

Elevated circulating levels of anandamide after administration of the transport inhibitor, AM404

The biological actions of the endogenous cannabinoid anandamide are terminated by carrier-mediated transport into neurons and astrocytes, followed by enzymatic hydrolysis. Anandamide transport is inhibited by the compound N-(4-hydroxyphenyl)arachidonylamide (AM404). AM404 potentiates several responses elicited by administration of exogenous anandamide, suggesting that it may also protect endogenous anandamide from inactivation. To test this hypothesis, we studied the effects of AM404 on the plasma levels of anandamide using high-performance liquid chromatography/mass spectrometry (HPLC/MS). Systemic administration of AM404 (10 mg kg-1 intraperitoneal, i.p.) caused a gradual increase of anandamide in rat plasma, which was significantly different from untreated controls at 60 and 120 min after drug injection. In plasma, both AM404 and anandamide were associated with a plasma protein, which we identified as albumin by non-denaturing polyacrylamide gel electrophoresis. AM404 (10 mg kg-1, i.p.) caused a time-dependent decrease of motor activity, which was reversed by the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide·hydrochloride (SR141716A, 0.5 mg kg-1, i.p). These results are consistent with the hypothesis that AM404 inhibits anandamide inactivation in vivo. (C) 2000 Elsevier Science B.V.

Involvement of reactive oxygen species in the oleoylethanolamide effects and its pyrazonilic analogue in melanoma cells

The search for more substances that effectively fight melanoma is extremely important, because of its aggressive nature. In this sense, the molecular hybridization is a promising strategy. The aim of this work is to evaluate whether the antiproliferative effect of the endocannabinoid oleoylethanolamide can be improved with the addition of a trifluoromethylated pyrazolinic nucleus on its structure in B16F10 cell line. The pyrazolinic analog was named oleoyl pyrazoline. We also compared the effects of oleoylethanolamide and that of the classic endocannabinoid anandamide (AEA). The cell viability was evaluated by MTT assay, the intracellular reactive oxygen species generation by fluorimetry, and apoptosis/necrosis by fluorescent microscopy. Also, α-tocopherol antioxidant was used to evaluate the involvement of reactive oxygen species in the cellular response. Although the effects of AEA occur in smaller concentrations, the results show that the effects of AEA and oleoylethanolamide were similar. The results showed a decrease in cell viability, induction of apoptosis and necrosis, and increased generation of reactive oxygen species by the oleoylethanolamide, while the oleoyl pyrazoline increased cell proliferation and decreased reactive oxygen species. Additionally, the effects of oleoylethanolamide in cell viability were decreased by inhibiting the generation of reactive oxygen species by α-tocopherol. Therefore, it is possible to suggest the involvement of reactive oxygen species in the effect of oleoylethanolamide in the B16F10 cells. Considering the great need to find substances that can fight melanoma and the lack of greater elucidation in the action mechanisms of cannabinoids and their analogs, this work provides important new information that could serve as reference to other studies.

Scalable synthesis of oleoyl ethanolamide by chemical amidation in a mixed solvent

Oleoyl ethanolamide is a lipid mediator that exhibits biological activity in animal and cell models. In this study, an effective process is described to synthesize oleoyl ethanolamide by chemical amidation with native oil used as an acyl donor in the presence of sodium methoxide. Reaction conditions were optimized. When the amidation reaction was conducted in a mixed solvent, by reacting 2 mmol high oleic sunflower oil and 20 mmol ethanolamine in the presence of 1.5 % sodium methoxide with agitation, >90 % fatty acid ethanolamide was formed after 3 h of reaction time. The fatty acid ethanolamide product was purified by a two-step crystallization process to prepare oleoyl ethanolamide. Highly pure oleoyl ethanolamide was obtained in a 70.3 % molar yield. The novelty of the work is the use of native oil as acyl donor and the mixed solvent used as the reaction media. The use of native oil avoids the formation of ion pairs with ethanolamine that can occur in other synthesis routes.

Novel analogues of arachidonylethanolamide (anandamide): Affinities for the CB1 and CB2 cannabinoid receptors and metabolic stability

Several analogues of the endogenous cannabinoid receptor ligand arachidonylethanolamide (anandamide) were synthesized and evaluated in order to study (a) the structural requirements for high-affinity binding to the CB1 and CB2 cannabinoid receptors and (b) their hydrolytic stability toward anandamide amidase. The series reported here was aimed at exploring structure-activity relationships (SAR) primarily with regard to stereoelectronic requirements of ethanolamido headgroup for interaction with the cannabinoid receptor active site. Receptor affinities, reported as K(i) values, were obtained by a standard receptor binding assay using [3H]CP- 55,940 as the radioligand, while stability toward the amidase was evaluated by comparing the K(i) of each analogue in the presence and absence of phenylmethanesulfonyl fluoride (PMSF), a serine protease blocker and inhibitor of anandamide amidase. Introduction of a methyl group in the 1'- and 2'-positions or substitution of the ethanolamido headgroup with a butylamido group gave analogues with vastly improved biochemical stability. This is accomplished in some cases with increased receptor affinity. Conversely, oxazolyl and methyloxazolyl headgroups led to low-affinity analogues. Substitution of the hydroxyl group with electronegative substituents such as fluoro, chloro, allyl, and propargyl groups significantly increased receptor affinity but did not influence the biochemical stability. The 2'-chloro analogue of anandamide was found to have the highest affinity for CB1. Additionally, reversing the positions of the carbonyl and NH in the amido group produces retro-anandamides possessing considerably higher metabolic stability. Replacement of the arachidonyl tail with oleyl or linoleyl results in analogues with low affinities for both receptors. All of the analogues in this study showed high selectivity for the CB1 receptor over the peripheral CB2 receptor. The most potent analogues were tested for their ability to stimulate the binding of [35S]GTPγS to G- proteins and were shown to be potent cannabimimetic agonists. The results are discussed in terms of pharmacophoric features affecting receptor affinity and enzymatic stability.

Pharmacological characterization of hydrolysis-resistant analogs of oleoylethanolamide with potent anorexiant properties

Oleoylethanolamide (OEA) is an endogenous lipid mediator that reduces food intake, promotes lipolysis, and decreases body weight gain in rodents by activating peroxisome proliferator-activated receptor-α (PPAR-α). The biological effects of OEA are terminated by two intracellular lipid hydrolase enzymes, fatty-acid amide hydrolase and N-acylethanolamine-hydrolyzing acid amidase. In the present study, we describe OEA analogs that resist enzymatic hydrolysis, activate PPAR-α with high potency in vitro, and persistently reduce feeding when administered in vivo either parenterally or orally. The most potent of these compounds, (Z)-(R)-9-octadecenamide,N-(2- hydroxyethyl, 1-methyl) (KDS-5104), stimulates transcriptional activity of PPAR-α with a half-maximal effective concentration (EC50) of 100 ± 21 nM (n = 11). Parenteral administration of KDS-5104 in rats produces persistent dose-dependent prolongation of feeding latency and postmeal interval (half-maximal effective dose, ED50 = 2.4 ± 1.8 mg kg-1 i.p.; n = 18), as well as increased and protracted tissue exposure compared with OEA. Oral administration of the compound also results in a significant tissue exposure and reduction of food intake in free-feeding rats. These results suggest that the endogenous high-affinity PPAR-α agonist OEA may provide a scaffold for the discovery of novel orally active PPAR-α ligands. Copyright

Prolyl endopeptidase inhibitory activity of unsaturated fatty acids

Prolyl endopeptidase (PEP, EC 3.4.21.26) is widely distributed in various organs, particularly in the brains of amnestic patients. Evaluation of PEP levels in postmortem brains of Alzheimer's disease patients revealed significant increases in PEP activity, suggesting that a specific PEP inhibitor can be a good candidate for an antiamnestic drug. In this study, mono- and polyunsaturated fatty acids were investigated to determine their role as PEP inhibitors. Oleic, linoleic, and arachidonic acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) showed PEP inhibitory activities (IC 50 values of 23.6 ± 0.4, 43.8 ± 1.8, 53.4 ± 1.2, 99.4 ± 1.2, and 46.2 ± 1.0 μM, respectively), indicating that they were effective PEP inhibitors, with inhibition constant (Ki) values of 26.7 ± 0.3, 51.0 ± 0.7, 91.3 ± 3.1, 247.5 ± 2.6, and 89.0 ± 2.3 μM, respectively. Oleic acid showed the highest PEP inhibitory activity. Dixon plots of PEP inhibition showed oleic, linoleic, and arachidonic acids, EPA, and DHA are noncompetitive inhibitors; despite higher IC50 values of these unsaturated fatty acids than strong natural inhibitors, they may have potential use in preventing memory loss.

Different roles for the acyl chain and the amine leaving group in the substrate selectivity of N-Acylethanolamine acid amidase

N-acylethanolamine acid amidase (NAAA) is an N-terminal nucleophile (Ntn) hydrolase that catalyses the intracellular deactivation of the endogenous analgesic and anti-inflammatory agent palmitoylethanolamide (PEA). NAAA inhibitors counteract this process and exert marked therapeutic effects in animal models of pain, inflammation and neurodegeneration. While it is known that NAAA preferentially hydrolyses saturated fatty acid ethanolamides (FAEs), a detailed profile of the relationship between catalytic efficiency and fatty acid-chain length is still lacking. In this report, we combined enzymatic and molecular modelling approaches to determine the effects of acyl chain and polar head modifications on substrate recognition and hydrolysis by NAAA. The results show that, in both saturated and monounsaturated FAEs, the catalytic efficiency is strictly dependent upon fatty acyl chain length, whereas there is a wider tolerance for modifications of the polar heads. This relationship reflects the relative stability of enzyme-substrate complexes in molecular dynamics simulations.

Chemical synthesizing method of N-oleoyl ethanolamine

The invention belongs to the technical field of N-oleoyl ethanolamine synthesizing and discloses a chemical synthesizing method of N-oleoyl ethanolamine. The chemical synthesizing method includes thesteps of S1, performing low-temperature stirring; S2, adding a mixed solution and N, N-dimethyl formamide; S3, adding triethylamine; S4, adding into amine mixed liquid, and stirring; S5, washing, extracting and performing vacuum concentration; S6, distilling to remove impurities; S7, silica gel column chromatography purification. The chemical synthesizing method has the advantages that the methodis simple, high in purification rate and applicable to large-batch factory production, and the synthesized pure N-oleoyl ethanolamine is free of impurities.

Improved fatty acid monoethanolamide synthesis method

The invention relates to an improved fatty acid monoethanolamide synthesis method, which comprises: 1) preparing a polystyrene resin containing a carboxyl activating agent; 2) carrying out a condensation reaction on the polystyrene resin obtained in the step (1) and fatty acid in the presence of a catalyst to obtain an immobilized active ester; and (3) in the presence of a solvent, carrying out a reaction on the immobilized active ester obtained in the step 2) and ethanolamine, carrying out simple filtration or centrifugation to remove the resin after completing the reaction, carrying out pressure reducing concentration on the obtained liquid phase, and carrying out vacuum drying to obtain the high-quality fatty acid monoethanolamide product. According to the present invention, the condensation reaction is performed under the normal temperature condition, the generation of the by-product is substantially reduced through the selection of the catalyst and the reaction parameters, and the yield of the reaction and the purity of the product are maximized; and with the synthesis method, the defects of more by-products, difficult purification and the like caused by unstable raw material, poor selectivity to ethanolamine and alkali high temperature condition in the prior art are overcome.