Synthesis of Fatty Acid Amides of Catechol Metabolites that Exhibit Antiobesity Properties

Almeida, Bruno; Joglar, Jesús; Rojas, María Jesús Luque; Decara, Juan; Bermúdez‐Silva, Francisco Javier; Macías-González, Manuel; Fitó, Montserrat; Romero-Cuevas, Miguel; Farré, Magı́; Covas, María Isabel; Fonseca, Fernando Rodrı́guez de; Torre, Rafael de la

doi:10.1002/cmdc.201000161

Cited by 8 publications

(13 citation statements)

References 30 publications

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“…Previously, we have reported that acute administration of OLHHA significantly decreases food intake in food-deprived Wistar rats ( Almeida et al, 2010 ). In the present study, we performed a repeated treatment of this dihydroxyphenyl derivative in a genetic model of obesity and NAFLD, followed by initial assays related to cardio- and hepatotoxicity.…”

Section: Discussionmentioning

confidence: 95%

“…In this regard, the activation of hepatic CB 1 is associated with an increase of de novo fatty acid synthesis, and this lipogenic response is abolished by CB 1 blockade ( Osei-Hyiaman et al, 2005 ). Given that the endocannabinoid system plays a main role in the regulation of energy homeostasis and that it has also been reported that OLHHA has affinity for the CB 1 ( Almeida et al, 2010 ), we evaluated the gene expression of the different components of this system in the liver of Zucker rats. Consistent with previous reports showing that the endocannabinoid system is altered in peripheral tissues in obese rats ( Izzo et al, 2009 , 2010 ), our results showed that this signaling system was dysregulated in the liver.…”

Section: Discussionmentioning

confidence: 99%

“…N -[1-(3,4-dihydroxyphenyl)propan-2-yl]oleamide (OLHHA) was synthesized as previously described ( Almeida et al, 2010 ). OLHHA was dissolved in a vehicle containing 5% Tween 80 in saline and injected intraperitoneally (i.p.)…”

Section: Methodsmentioning

confidence: 99%

“…, 2008 ; Pérez-Fernández et al, 2011 ). Recently, we have synthesized and characterized a series of compounds derived from fatty acids conjugated with 3,4-methylenedioxymethamphetamine metabolites as anti-obesity drugs ( Almeida et al, 2010 ). Among these novel molecules, the N -[1-(3,4-dihydroxyphenyl)propan-2-yl]oleamide (OLHHA) has inhibitory effects on feeding behaviour and produces antioxidant effects, acting as a potent inhibitor of low-density lipoprotein oxidation, as disclosed in the International Patent Application No.…”

Section: Introductionmentioning

confidence: 99%

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Treatment with a novel oleic-acid–dihydroxyamphetamine conjugation ameliorates non-alcoholic fatty liver disease in obese Zucker rats

Decara

Pavón

Suárez

et al. 2015

Disease Models &Amp; Mechanisms

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Fatty liver disease is one of the main hepatic complications associated with obesity. To date, there are no effective treatments for this pathology apart from the use of classical fibrates. In this study, we have characterized the in vivo effects of a novel conjugation of oleic acid with an amphetamine derivative (OLHHA) in an animal model of genetic obesity. Lean and obese Zucker rats received a daily intraperitoneal administration of OLHHA (5 mg kg−1) for 15 days. Plasma and liver samples were collected for the biochemical and molecular biological analyses, including both immunohistochemical and histological studies. The expression of key enzymes and proteins that are involved in lipid metabolism and energy homeostasis was evaluated in the liver samples. The potential of OLHHA to produce adverse drug reactions or toxicity was also evaluated through the monitoring of interactions with hERG channel and liver cytochrome. We found that OLHHA is a drug with a safe pharmacological profile. Treatment for 15 days with OLHHA reduced the liver fat content and plasma triglyceride levels, and this was accompanied by a general improvement in the profile of plasma parameters related to liver damage in the obese rats. A decrease in fat accumulation in the liver was confirmed using histological staining. Additionally, OLHHA was observed to exert anti-apoptotic effects. This hepatoprotective activity in obese rats was associated with an increase in the mRNA and protein expression of the cannabinoid type 1 receptor and a decrease in the expression of the lipogenic enzymes FAS and HMGCR primarily. However, changes in the mRNA expression of certain proteins were not associated with changes in the protein expression (i.e. L-FABP and INSIG2). The present results demonstrate that OLHHA is a potential anti-steatotic drug that ameliorates the obesity-associated fatty liver and suggest the potential use of this new drug for the treatment of non-alcoholic fatty liver disease.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Treatment with a novel oleic-acid–dihydroxyamphetamine conjugation ameliorates non-alcoholic fatty liver disease in obese Zucker rats

Decara

Pavón

Suárez

et al. 2015

Disease Models &Amp; Mechanisms

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“…We consider that the ether derivatives of hydroxytyrosol could have a significant importance in obesity management because appetite and lipid metabolism could be simultaneously regulated. 18 A new route for the synthesis of hydroxytyrosol ether derivatives ( Figure 3) with natural unsaturated derived fatty alcohols such as oleic and linoleic alcohol is proposed. It is postulated that newly synthesized compounds may have LDL antioxidant activity with a potency similar to that of hydroxytyrosol.…”

Section: ■ Introductionmentioning

confidence: 99%

Unsaturated Fatty Alcohol Derivatives of Olive Oil Phenolic Compounds with Potential Low-Density Lipoprotein (LDL) Antioxidant and Antiobesity Properties

Cotrim

Joglar

Rojas

et al. 2012

J. Agric. Food Chem.

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A new route for the synthesis of fatty alcohol derivatives of hydroxytyrosol and other olive oil phenolic compounds was developed to allow the preparation of unsaturated derivatives. The biological activity of synthesized compounds was evaluated. Most of the compounds presented a significant antioxidant activity on low-density lipoprotein (LDL) particles. The activity of the tested products was significantly influenced by the number and position of unsaturations as well as modifications on the polar head of the synthesized compounds. Some of them presented modulation of food intake in rats and, due to their molecular similarity with CB(1) endogenous ligands, the endocannabinoid system and PPAR-α were also evaluated as potential targets. The pharmacodynamics could not be totally explained by CB(1) and PPAR-α receptor interactions because only two of the four compounds with biological activity showed a CB(1) activity and all of them presented low PPAR-α affinity, not justifying its whole in vivo activity. The hydroxytyrosol linoleylether (7) increased LDL resistance to oxidation with a capacity similar to that of hydroxytyrosol and was the most active in vivo compound with a hypophagic effect comparable to that of oleoylethanolamine. We consider that this compound could be a good lead compound for future drug development in obesity treatments.

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Metallic magnesium: an efficient catalyst toward N-aryl and N-alkyl substituted amides directly from aliphatic carboxylic acids

Yıldırım

2014

Monatsh Chem

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Synthesis of Fatty Acid Amides of Catechol Metabolites that Exhibit Antiobesity Properties

Cited by 8 publications

References 30 publications

Treatment with a novel oleic-acid–dihydroxyamphetamine conjugation ameliorates non-alcoholic fatty liver disease in obese Zucker rats

Treatment with a novel oleic-acid–dihydroxyamphetamine conjugation ameliorates non-alcoholic fatty liver disease in obese Zucker rats

Unsaturated Fatty Alcohol Derivatives of Olive Oil Phenolic Compounds with Potential Low-Density Lipoprotein (LDL) Antioxidant and Antiobesity Properties

Metallic magnesium: an efficient catalyst toward N-aryl and N-alkyl substituted amides directly from aliphatic carboxylic acids

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