MDMA (3,4-Methylenedioxymethamphetamine) Analogues as Tools to Characterize MDMA-Like Effects: An Approach to Understand Entactogen Pharmacology

Abstract

Besides stimulants and hallucinogens, whose psychotropic effects are shared by many structurally related molecules exhibiting different efficacies and potencies in humans, the phenylisopropylamine MDMA (3,4-methylenedioxymethamphetamine, XTC, “Ecstasy”) is the prototypical representative of a separate class of psychotropic substance, able to elicit the so-called entactogenic syndrome in healthy humans. This reversible altered state of consciousness, usually described as an “open mind state”, may have relevant therapeutic applications, both in psychotherapy and as a pharmacological support in many neuropsychiatric disorders with a high rate of treatment failure. Nevertheless, a comprehensive and systematic exploration of the structure-activity relationships associated with entactogenic activity has remained incomplete and controversial, highlighting the possibility that MDMA might represent a pharmacological rarity in the field of psychotropics. As the latter is still an open question, the pharmacological characterization of MDMA analogues remains the logical strategy to attempt the elucidation of the structural requirements needed to elicit typical MDMA-like effects. Intriguingly, almost no experimental evidence supports the existence of actual MDMA analogues that truly resemble the whole pharmacological profile of MDMA, probably due to its complex (and partially not fully understood) mechanism of action that includes a disruption of monoaminergic neurotransmission. The present review presents a brief summary of the pharmacology of MDMA, followed by the evidence accumulated over the years regarding the characterization of classical structurally related MDMA analogues in different models and how this state of the art highlights the need to develop new and better MDMA analogues.

Aromatic Bromination Abolishes the Psychomotor Features and Pro-social Responses of MDMA (“Ecstasy”) in Rats and Preserves Affinity for the Serotonin Transporter (SERT)

“…The results obtained in the present work agree with this assumption, as shown by the differences between MDMA and 2-Br-4,5-MDMA in key ecstasy-like behavioral paradigms. Regarding the latter, it should be noted that the behavioral characterization of ecstasy has been attempted in different animal models, producing heterogeneous results that depend on several factors, such as dosage regimen, animal species or administration routes (Sáez-Briones and Hernández, 2013; Dunlap et al, 2018). Nevertheless, and for the purpose of the present work, a behavioral profile of MDMA in rats after acute administration based on complete dose-effect curves under the same experimental conditions has been used to evaluate the influence of aromatic bromination (Quinteros-Muñoz et al, 2010).…”

“…Nevertheless, and despite its relevance, the pharmacological characterization of the effects of aromatic halogenation on the mode of binding at SERT referred to MDMA remains fragmentary and incomplete. For instance, aromatic bromination at C(2) to afford 1-(2-bromo-4,5-methylendioxyphenyl)-2-methylaminopropane (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.…”

Acute Effects of the Novel Psychoactive Drug 2C-B on Emotions

“…Our results indicate that 2C-B has specific effects on emotional processing and mood states which permit its classification as an entactogenic substance with psychedelic and hallucinogenic characteristics. Entactogenic effects are characterized as an “open mind” state with properties including an increase in self-awareness, the sensation “to produce a touching within,” introspection, elevated sensory perception, and enhanced prosocial effect [ 54 ]. However, its influence with respect to the worsening of the affective perception of faces does not point to empathogenic qualities and, despite the slight effects observed in cardiovascular measurements, the result of the verbal fluency test is not typical of stimulants.…”

Induced fit, ensemble binding space docking and Monte Carlo simulations of MDMA ‘ecstasy’ and 3D pharmacophore design of MDMA derivatives on the human serotonin transporter (hSERT)

“…Due to its rare and reliable ability to produce pro-social states, reduce fear responses, promote introspection, empathy and beneficial emotional processing, 3,4-methylenedioxy-methamphetamine, MDMA or 'ecstasy' is the drug with arguably the most potential to usher in a new progressive era in psychedelic science (S aez-Briones and Hern andez, 2013;Dunlap et al, 2018;Curry et al, 2018;Inserra et al, 2021). Proposed to be under the broader category of 'psychedelics' (Dunlap et al, 2018), the drug class 'entactogen' was coined to classify MDMA, MBDB (3,, MDA (3, and MDAI (5,, based on early psychiatric use, animal behavioural and human subjective effects, as well as for its departure from the classical SAR (Structure-Activity Relationship) of hallucinogens (Nichols, 1986).…”

“…S1, comprised by sub-sites A, B and C. NSSs undergo a conformational transition from an outward-open into an inward-open state subsequently releasing the neurotransmitter to the cytoplasm (Navratna and Gouaux, 2019). Indeed, the role of the SERT in the mechanism of action of MDMA is preponderant since the entactogenic effects of this drug are mediated by the release of 5HT (Nichols, 1986;Johnson et al, 1986;Tancer and Johanson, 2007;S aez-Briones and Hern andez, 2013) and neuroimaging reveals that SERT density is decreased in brain regions of chronic MDMA users (Müller et al, 2019). Importantly, there is evidence that the compound-induced substrate translocation (5HT release) and macromolecular conformational changes associated to uptake inhibition critically depend on the initial binding mode of the SERT ligands (Sandtner et al, 2016).…”