- N-morpholino- and N-diethyl-analogues of palmitoylethanolamide increase the sensitivity of transfected human vanilloid receptors to activation by anandamide without affecting fatty acid amidohydrolase activity
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The abilities of 19 analogues of palmitoylethanolamide and two analogues of oleoylethanolamide to affect the Ca2+ influx into human embryonic kidney cells expressing the human vanilloid receptor (hVR1-HEK293 cells) in response to anandamide (AEA) have been investigated using a FLIPR assay and a bovine serum albumin-containing assay medium. Only palmitoylethanolamide produced any effect in the absence of AEA. The ability of palmitoylethanolamide to potentiate the response to AEA was retained when the N-CH2CH2OH group was replaced by N-CH2CH2Cl,whereas replacement with N-alkyl substituents [from -H up to -(CH2)12CH3] resulted either in a reduction or in a complete loss of this activity. The tertiary amide N-(CH2CH3)2 (19) and N-morpholino (20) analogues of palmitoylethanolamide potentiated the response to 1 μM AEA to a greater degree than the parent compound, whereas the N-(CH3)2 analogue was inactive. 19 and 20 produced leftward shifts in the dose-response curve for AEA activation of Ca2+ influx into hVR1-HEK293 cells. EC50 values for AEA to produce Ca2+ influx into hVR1-HEK293 cells were 1.1, 1.1, 0.54 and 0.36 μM in the presence of 0, 1, 3 and 10 μM 19, respectively. The corresponding values for 20 were 1.5, 1.3, 0.77 and 0.17 μM, respectively. The compounds did not affect the dose-response curves to capsaicin. The ability of oleoylethanolamide to potentiate AEA is retained by the N-CH2CH3 and N-CH(CH3)2 analogues (22 and 23, respectively). 22 and 23 produced a small (~25%) inhibition of the binding of [3H]-CP55,940 and [3H]-WIN 55,212-2 to CB1 and CB2 receptors, respectively, expressed in CHO cells. The compounds inhibited the metabolism of 2 μM [3H]-AEA by rat brain fatty acid amidohydrolase with IC50 values of 5.6 and 11 μM, respectively. In contrast, 19 and 20 were without effect on either binding to CB receptors or fatty acid amidohydrolase activity. Minor reductions in the accumulation of 10 μM [3H]-AEA into C6 glioma cells were seen at 10 μM concentrations of 19 and 20. It is concluded that 19 and 20 selectively enhance AEA effects upon VR1 receptors without potentially confounding effects upon CB receptors or fatty acid amidohydrolase activity.
- Vandevoorde, Severine,Lambert, Didier M.,Smart, Darren,Jonsson, Kent-Olov,Fowler, Christopher J.
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- A catalyst-free, waste-less ethanol-based solvothermal synthesis of amides
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A green, one-pot approach based on the solvothermal amidation of carboxylic acids with amines has been developed for the synthesis of diverse aliphatic and aromatic amides. It does not require the use of catalysts or coupling reagents and it occurs in the presence of ethanol that has been proved to have a key role in the process. The proposed strategy is also extendable to biologically active amides and could represent a low-cost and waste-less alternative to the common synthetic pathways.
- Dalu, Francesca,Scorciapino, Mariano A.,Cara, Claudio,Luridiana, Alberto,Musinu, Anna,Casu, Mariano,Secci, Francesco,Cannas, Carla
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supporting information
p. 375 - 381
(2018/02/07)
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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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