- Synthesis and biological evaluation of novel amides of polyunsaturated fatty acids with dopamine
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New amides of different fatty acids from the C18, C20, and C22 series with dopamine were synthesized. Pharmacological characterization in binding assays with rat brain membrane preparations and in the 'tetrad' of cannabinoid behavioral tests showed that, for these compounds, cannabinoid-like activity was dependent on the fatty acid moiety. Our data demonstrate that polyenoic fatty acid amides with dopamine comprise a new family of synthetic cannabimimetics.
- Bezuglov, Vladimir,Bobrov, Mikhail,Gretskaya, Natalia,Gonchar, Alla,Zinchenko, Galina,Melck, Dominique,Bisogno, Tiziana,Di Marzo, Vincenzo,Kuklev, Dmitry,Rossi, Jean-Claude,Vidal, Jean-Pierre,Durand, Thierry
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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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- N-docosahexaenoyl, 3 hydroxytyramine: A dopaminergic compound that penetrates the blood-brain barrier and suppresses appetite
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Fatty acids with varying chain lengths (2-22 carbon atoms long) and degrees of unsaturation (0-6 double bonds) were used to synthesize dopaminergic compounds for a study of the carrier mediated transport of dopamine (DA) to the brain. The most active carrier was the all cis C22:6 fatty acid [docosahexaenoic acid,( DHA)]which increased DA uptake through the blood-brain barrier by greater than 7.5 fold. The DHA-DA compound, NMI 8739, depressed the general locomotor activity of mice in a dose dependent manner. It also suppressed the appetite of Balb c mice and Charles River rats by 50% and 95% respectively at a dose of 10 mg/kg. Daily administration of NMI-8739 for a three week period did not induce tolerance. These results demonstrate DHA's potential for the carrier mediated transport of small molecules to the brain.
- Shashoua, Victor E.,Hesse, Gary W.
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p. 1347 - 1357
(2007/10/03)
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- Inhibition of in vitro prostaglandin and leukotriene biosyntheses by cinnamoyl-β-phenethylamine and N-acyldopamine derivatives
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N-trans- and N-cis-Feruloyltyramines were isolated as the inhibitors of in vitro prostaglandin (PG) synthesis from an Indonesian medicinal plant, Ipomoea aquatica (Convolvulaceae). In order to clarify structure activity relationships, cinnamoyl-β-phenethylamines with possible combinations of naturally occurring cinnamic acids and β-phenethylamines were synthesized and tested for their inhibitory activities against PG synthetase and arachidonate 5-lipoxygenase. The compounds containing catechol groups such as N-caffeoyl-β-phenethylamine (CaP) showed higher inhibitory effects on PG synthetase. The catechol group was found to M essential for the inhibition of arachidonate 5-lipoxygenase. The investigation of concentration dependent effects on PG biosynthesis revealed that CaP enhanced PG biosynthesis at a lower concentration range, whereas it inhibited the reaction at a higher concentration. The effects of CaP on each reaction step were investigated with purified PG endoperoxide synthase and microsomal PG synthetase. CaP inhibited the cyclooxygenase reaction, while it enhanced the hydroperoxidase reaction. N-Acyldopamines which contain catechol and lipophylic group were synthesized from dopamine and fatty acids to test their inhibitory effects on arachidonate 5-lipoxygenase. N-Linoleoyldopamine was the most active compound and its IC50 value was 2.3 nM in our assay system, in which an IC50 value of AA 861, a specific inhibitor of 5-lipoxygenase, was 8 nM.
- Tseng,Iwakami,Mikajiri,Shibuya,Hanaoka,Ebizuka,Padmawinata,Sankawa
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p. 396 - 400
(2007/10/02)
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