Abstract
The entactogen MDMA (3,4-methylenedioxy-methamphetamine, “Ecstasy”) exerts its psychotropic effects acting primarily as a substrate of the serotonin transporter (SERT) to induce a non-exocytotic release of serotonin. Nevertheless, the roles of specific positions of the aromatic ring of MDMA associated with the modulation of typical entactogenic effects, using analogs derived from the MDMA template, are still not fully understood. Among many possibilities, aromatic halogenation of the phenylalkylamine moiety may favor distribution to the brain due to increased lipophilicity, and sometimes renders psychotropic substances of high affinity for their molecular targets and high potency in humans. In the present work, a new MDMA analog brominated at C(2) of the aromatic ring (2-Br-4,5-MDMA) has been synthesized and pharmacologically characterized in vitro and in vivo. First, binding competition experiments against the SERT-blocker citalopram were carried out in human platelets and compared with MDMA. Besides, its effects on platelet aggregation were performed in platelet enriched human plasma using collagen as aggregation inductor. Second, as platelets are considered an appropriate peripheral model for estimating central serotonin availability, the functional effects of 2-Br-4,5-MDMA and MDMA on ATP release during human platelet aggregation were evaluated. The results obtained showed that 2-Br-4,5-MDMA exhibits higher affinity for SERT than MDMA and fully abolishes both platelet aggregation and ATP release, resembling the pharmacological profile of citalopram. Subsequent in vivo evaluation in rats at three dose levels showed that 2-Br-4,5-MDMA lacks all key MDMA-like behavioral responses in rats, including hyperlocomotion, enhanced active avoidance conditioning responses and increased social interaction. Taken together, the results obtained are consistent with the notion that 2-Br-4,5-MDMA should not be expected to be an MDMA-like substrate of SERT, indicating that aromatic bromination at C(2) modulates the pharmacodynamic properties of the substrate MDMA, yielding a citalopram-like compound.
Highlights
The entactogen MDMA (3,4-methylenedioxymethamphetamine, Figure 1A), known as “Ecstasy,” engenders in humans an altered state of consciousness described as a feeling of heightened self-acceptance and empathy with other persons without impairing cognitive or orientation capabilities, while decreasing fear responses (Green et al, 2003)
Effects of MDMA and 2-Br-4,5-MDMA on [3H]-Citalopram Binding to Platelet Membranes
Drug competition curves for [3H]-citalopram binding (Figure 1B) allowed the inhibition constants (Ki) of MDMA and 2-Br-4,5-MDMA to be calculated for the site that is labeled by [3H]-citalopram, which most likely is serotonin transporter (SERT)
Summary
The entactogen MDMA (3,4-methylenedioxymethamphetamine, Figure 1A), known as “Ecstasy,” engenders in humans an altered state of consciousness described as a feeling of heightened self-acceptance and empathy with other persons without impairing cognitive or orientation capabilities, while decreasing fear responses (Green et al, 2003). It was further found that the ring-methylated MDA derivatives 1-(2-methyl-3,4-methylenedioxyphenyl)- and 1-(3-methyl-4,5methylenedioxyphenyl)-2-aminopropane are fairly potent 5-HT releasers in rats and substitute, at low doses, for the entactogen-like MBDB and MMAI in the drug discrimination paradigm, whereas the positional isomer 1(2-methyl-4,5-methylenedioxyphenyl)-2-aminopropane is four times less potent than MMAI and only substitutes partially for MBDB (Parker et al, 1998) This evidence suggests that rational modifications of the benzene ring of MDMA can lead to potentially new analogs sharing some of the distinctive MDMAlike effects. Aromatic bromination at C(2) to afford 1-(2-bromo-4,5-methylendioxyphenyl)-2methylaminopropane (2-Br-4,5-MDMA) has been proposed as an approach to an analog that might exhibit entactogenic-like properties (Sáez-Briones and Hernández, 2013) This notion is supported by some members of the heterogenous group of psychotropic phenylalkylamines, including MDMA. We hypothesize that bromine substitution may increase the pharmacological features of MDMA, including SERT affinity, the ability to act as a SERT substrate and the distinctive behavioral effects already known for Ecstasy
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