Journal Article

Structure-activity relationships of serotonergic 5-MeO-DMT derivatives: insights into psychoactive and thermoregulatory properties

Ketsela, Gabriel, Puigseslloses, Pol, Niello, Marco, Camarasa, Jordi, Nadal-Gratacós, Núria, Pubill, David, Holy, Marion, López-Arnau, Raúl, Berzosa, Xavier, Estrada-Tejedor, Roger, Weiss, Nicola, Islam, Mohammad Nazmul, Sitte, Harald H., Escubedo, Elena

2024

Overview

Recent studies have sparked renewed interest in the therapeutic potential of psychedelics for treating depression and other mental health conditions. Simultaneously, the novel psychoactive substances (NPS) phenomenon, with a huge number of NPS emerging constantly, has changed remarkably the illicit drug market, being their scientific evaluation an urgent need. Thus, this study aims to elucidate the impact of amino-terminal modifications to the 5-MeO-DMT molecule on its interactions with serotonin receptors and transporters, as well as its psychoactive and thermoregulatory properties. Our findings demonstrated, using radioligand binding methodologies, that all examined 5-MeO-tryptamines exhibited selectivity for 5-HT1AR over 5-HT2AR. In fact, computational docking analyses predicted a better interaction in the 5-HT1AR binding pocket compared to 5-HT2AR. Our investigation also proved the interaction of these compounds with SERT, revealing that the molecular size of the amino group significantly influenced their affinity. Subsequent experiments involving serotonin uptake, electrophysiology, and superfusion release assays confirmed 5-MeO-pyr-T as the most potent partial 5-HT releaser tested. All tested tryptamines elicited, to some degree, the head twitch response (HTR) in mice, indicative of a potential hallucinogenic effect and mainly mediated by 5-HT2AR activation. However, 5-HT1AR was also shown to be implicated in the hallucinogenic effect, and its activation attenuated the HTR. In fact, tryptamines that produced a higher hypothermic response, mediated by 5-HT1AR, tended to exhibit a lower hallucinogenic effect, highlighting the opposite role of both 5-HT receptors. Moreover, although some 5-MeO-tryptamines elicited very low HTR, they still act as potent 5-HT2AR agonists. In summary, this research offers a comprehensive understanding of the psychopharmacological profile of various amino-substituted 5-MeO-tryptamines, keeping structural aspects in focus and accumulating valuable data in the frame of NPS. Moreover, the unique characteristics of some 5-MeO-tryptamines render them intriguing molecules as mixed-action drugs and provide insight within the search of non-hallucinogenic but 5-HT2AR ligands as therapeutical agents.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/95 / 631/337 / 631/378 / 631/477 / 64/60 / 9/74 / 96/106 / 96/95 / 96/98 / Animals / Behavioral Sciences / Biological Psychology / Body Temperature Regulation - drug effects / Electrophysiology / Fatalities / Hallucinogens - pharmacology / HEK293 Cells / Humans / Male / Medical research / Medicine / Medicine & Public Health / Mental disorders / Methoxydimethyltryptamines - metabolism / Methoxydimethyltryptamines - pharmacology / Mice / Molecular Docking Simulation - methods / Neurosciences / Pharmacology / Pharmacotherapy / Psychedelic drugs / Psychiatry / Psychotropic drugs / Psychotropic Drugs - pharmacology / Receptor mechanisms / Receptor, Serotonin, 5-HT1A - drug effects / Receptor, Serotonin, 5-HT1A - metabolism / Receptor, Serotonin, 5-HT2A - drug effects / Receptor, Serotonin, 5-HT2A - metabolism / Receptors, Serotonin - drug effects / Receptors, Serotonin - metabolism / Serotonin / Serotonin - metabolism / Serotonin Plasma Membrane Transport Proteins - drug effects / Serotonin Plasma Membrane Transport Proteins - metabolism / Serotonin S1 receptors / Serotonin S2 receptors / Serotonin transporter / Structure-Activity Relationship / Structure-activity relationships