3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a psychostimulant widely abused among young people. MDMA exhibits distinct pharmacological properties, collectively described as entactogenic, which differentiate it from classic amphetamines (Nichols, 1986). MDMA produces acute and long-term serotonergic neurotoxicity in rodents, primates, and, possibly, in humans, with the severity of toxicity dependent on the dose and frequency of administration (Green et al., 2003). Such neurotoxicity is demonstrated by a decrease in tryptophan hydroxylase activity (Stone et al., 1988), a reduction in serotonin content, a dose-dependent persistent decrease in the number of 5-HT transporter sites and 5-HT receptors in several regions of the brain (Aguirre et al., 1995;Ricaurte et al., 2000), and an impairment of central 5-HT function (Barrionuevo et al., 2000).

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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A series of fatty acid amides of 3,4-methylenedioxymethamphetamine (MDMA) catechol metabolites were synthesized in order to evaluate their biological activities. Upon administration, all synthesized compounds resulted in negative modulation of food intake in rats. The most active compounds have affinity for the CB(1) receptor and/or PPAR-α; part of their biological activity may be caused by these double interactions.