- Design, synthesis and CoMFA studies of OEA derivatives as FAAH inhibitors
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A total of 26 novel oleoylethanolamide derivatives were designed, synthesized, and characterized. All synthesized targets compounds were screened for their inhibitory activities against fatty acid amide hydrolase. Among of them, 13 compounds inhibit fatty acid amide hydrolase by 50% at the concentration of 100 μM. Of these compounds, the most active one is compound 9, which inhibit fatty acid amide hydrolase activity 98.35% at the concentration of 100 μM. Comparative molecular field analysis analyzes were performed based on obtained biological activities data and resulted in a statistically reliable comparative molecular field analysis model with high predictive abilities (r2 = 0.978, q2 = 0.613).
- Han, Daxiong,Wang, Biyan,Jin, Hui,Wang, Haiyan,Chen, Meimei
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p. 2951 - 2966
(2017/10/06)
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- Pharmaceuticals and Surfactants from Alga-Derived Feedstock: Amidation of Fatty Acids and Their Derivatives with Amino Alcohols
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Amidation of renewable feedstocks, such as fatty acids, esters, and Chlorella alga based biodiesel, was demonstrated with zeolites and mesoporous materials as catalysts and ethanolamine, alaninol, and leucinol. The last two can be derived from amino acids present in alga. The main products were fatty alkanol amides and the corresponding ester amines, as confirmed by NMR and IR spectroscopy. Thermal amidation of technical-grade oleic acid and stearic acid at 180°C with ethanolamine were non-negligible; both gave 61% conversion. In the amidation of stearic acid with ethanolamine, the conversion over H-Beta-150 was 80% after 3 h, whereas only 63% conversion was achieved for oleic acid; this shows that a microporous catalyst is not suitable for this acid and exhibits a wrinkled conformation. The highest selectivity to stearoyl ethanolamide of 92% was achieved with mildly acidic H-MCM-41 at 70% conversion in 3 h at 180°C. Highly acidic catalysts favored the formation of the ester amine, whereas the amide was obtained with a catalyst that exhibited an optimum acidity. The conversion levels achieved with different fatty acids in the range C12-C18 were similar; this shows that the fatty acid length does not affect the amidation rate. The amidation of methyl palmitate and biodiesel gave low conversions over an acidic catalyst, which suggested that the reaction mechanism in the amidation of esters was different. Pores versus acidity: The structures and properties of zeolites and mesoporous materials are investigated as catalysts for the amidation of renewable feedstocks, such as fatty acids, esters, and Chlorella alga based biodiesel, with ethanolamine, alaninol, and leucinol as nitrogen sources.
- Tkacheva, Anastasia,Dosmagambetova, Inkar,Chapellier, Yann,M?ki-Arvela, P?ivi,Hachemi, Imane,Savela, Risto,Leino, Reko,Viegas, Carolina,Kumar, Narendra,Er?nen, Kari,Hemming, Jarl,Smeds, Annika,Murzin, Dmitry Yu.
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p. 2670 - 2680
(2015/09/02)
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- Evaluation of endogenous fatty acid amides and their synthetic analogues as potential anti-inflammatory leads
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A series of endogenous fatty acid amides and their analogues (1-78) were prepared, and their inhibitory effects on pro-inflammatory mediators (NO, IL-1β, IL-6, and TNF-α) in LPS-activated RAW264.7 cells were evaluated. Their inhibitory activity on the pro-inflammatory chemokine MDC in IFN-γ-activated HaCaT cells was also examined. The results showed that the activity is strongly dependent on the nature of the fatty acid part of the molecules. As expected, the amides derived from enone fatty acids showed significant activity and were more active than those derived from other types of fatty acids. A variation of the amine headgroup also altered bioactivity profile remarkably, possibly by modulating cell permeability. Regarding the amine part of the molecules, N-acyl dopamines exhibited the most potent activity (IC50 ～2 μM). This is the first report of the inhibitory activity of endogenous fatty acid amides and their analogues on the production of nitric oxide, cytokines (IL-1β, IL-6, and TNF-α) and the chemokine MDC. This study suggests that the enone fatty acid-derived amides (such as N-acyl ethanolamines and N-acyl amino acids) and N-acyl dopamines may be potential anti-inflammatory leads.
- Dang, Hung The,Kang, Gyeoung Jin,Yoo, Eun Sook,Hong, Jongki,Choi, Jae Sue,Kim, Hyung Sik,Chung, Hae Young,Jung, Jee H.
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experimental part
p. 1520 - 1527
(2011/03/23)
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- Pharmacological characterization of hydrolysis-resistant analogs of oleoylethanolamide with potent anorexiant properties
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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
- Astarita, Giuseppe,Di Giacomo, Barbara,Gaetani, Silvana,Oveisi, Fariba,Compton, Timothy R.,Rivara, Silvia,Tarzia, Giorgio,Mor, Marco,Piomelli, Daniele
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p. 563 - 570
(2008/01/27)
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- Novel analogues of arachidonylethanolamide (anandamide): Affinities for the CB1 and CB2 cannabinoid receptors and metabolic stability
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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.
- Lin, Sonyuan,Khanolkar, Atmaram D.,Fan, Pusheng,Goutopoulos, Andreas,Qin, Ce,Papahadjis, Demetris,Makriyannis, Alexandras
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p. 5353 - 5361
(2007/10/03)
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