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.2024 Aug;29(8):2346-2358.
doi: 10.1038/s41380-024-02506-8. Epub 2024 Mar 14.

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

Affiliations

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

Pol Puigseslloses et al. Mol Psychiatry.2024 Aug.

Abstract

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.

© 2024. The Author(s).

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. In vitro assays.
a 5-HT2AR-mediated calcium mobilization assay of the tested 5-MeO-tryptamines and reference compounds 5-HT (full agonist) and dopamine (DA; partial agonist). Data are expressed as means ± SD forN ≥ 3 experiments.b 5-HT uptake inhibition at SERT. Data are expressed as percentage of control uptake (absence of tryptamine), as means ± SD forN ≥ 3 experiments.c–f Effects of 5-MeO-DMT, 5-MeO-MET, 5-MeO-DET and 5-MeO-pyr-T on transport-mediated batch release of preloaded [3H]5-HT from HEK293 cells stably expressing SERT. *p < 0.05, **p < 0.01, ***p < 0.001 vs release in absence of monensin (mixed-effects model, employing Šidák’s correction;N = 5).g–j Whole-cell patch clamp experiments used to identify tryptamine-induced SERT-mediated inwardly directed currents in HEK293 cells (N = 5).k–n Representative single-cell traces showing currents elicited by 10 µM of 5-MeO-DMT, 5-MeO-MET, 5-MeO-DET, and 5-MeO-pyr-T. Data are presented as means ± SD forN = 5 independent experiments.o Concentration-response relationship of 5-MeO-pyr-T measured in superfusion release assays at different concentrations, as percentage of total efflux (N = 5). KHB and pCA were used as control substances. *p < 0.05, **p < 0.01, ***p < 0.001 versus KHB,###p < 0.001 vs pCA (Tukey’s test).
Fig. 2
Fig. 2. Interaction mechanism of 5-MeO-tryptamines at 5-HT receptors.
a Ligand efficiency of the compounds when bound to 5-HT1AR or 5-HT2AR.b Binding pockets of 5-HT1AR (blue) and 5-HT2AR (purple).c Interaction between the indole scaffold and Thr121 of 5-MeO-DMT.d,e Predicted binding mechanism of 5-MeO-MET and 5-MeO-DIPT at 5-HT1AR. Green zones correspond to hydrophobic regions and purple zones correspond to hydrophilic regions within the pocket.f,g Spatial orientation of 5-MeO-MET and 5-MeO-DIPT in the 5-HT2AR pocket.
Fig. 3
Fig. 3. Head Twitch Response.
a–j Number of head-twitch events during a 10-min period for all the tested tryptamines. Data are presented as means ± SD. *p < 0.05, **p < 0.01, ***p < 0.001 vs control group (Kruskall-Wallis with Dunn’s test).N = 8–10 mice per group.k Correlation between HT2AR-mediated calcium mobilization potency (in vitro) and HTR potency (in vivo), with 95% CI.l Representative example of the number of head twitches after 5-MeO-pyr-T injection (i.p., 10 mg/kg) with or without 5-HT1AR or 5-HT2AR antagonist pretreatment, WAY100635 (s.c., 1 mg/kg; WAY) or ketanserin (s.c., 1 mg/kg; KS), respectively. Data are presented as means ± SD. ***p < 0.001 vs control group,##p < 0.01,###p < 0.001 vs group receiving only 5-MeO-pyr-T (ANOVA with Tuckey’s test).N = 8–10 mice per group.
Fig. 4
Fig. 4. Hypothermic response.
a–j Change in core body temperature 60 min post injection. Data are presented as means ± SD. *p < 0.05, **p < 0.01, ***p < 0.001 vs control saline group (ANOVA with Dunnet’s test or Kruskall-Wallis with Dunn’s test).N = 8–10 mice per group.k Correlation between affinity for 5-HT1AR (in vitro) and potency in the hypothermic response (in vivo).l Correlation between maximal effects in the hypothermic response and HTR. Discontinuous lines represent 95% CI.m,n Representatives examples (5-MeO-pyr-T and 5-MeO-EIPT, i.p., 10 mg/kg) of the core body temperature measured after 60 min of tryptamine injection with or without WAY100635 pretreatment (s.c., 1 mg/kg; WAY). Data are shown as means ± SD. **p < 0.01, ***p < 0.001 vs control saline group.##p < 0.01,###p < 0.001 vs group receiving only tryptamine (ANOVA with Tuckey’s test).N = 8–10 mice per group.
Fig. 5
Fig. 5. Horizontal locomotor activity.
a–j Total distance traveled in a 30-min period. Data are presented as means ± SD. *p < 0.05, **p < 0.01, ***p < 0.001 vs control saline group (ANOVA with Dunnet’s test or Kruskall-Wallis with Dunn’s test).N = 8–10 mice per group.
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References

    1. Catalani V, Corkery JM, Guirguis A, Napoletano F, Arillotta D, Zangani C, et al. Psychonauts’ psychedelics: a systematic, multilingual, web-crawling exercise. Eur Neuropsychopharmacol. 2021;49:69–92. - DOI - PubMed
    1. EMCDDA. European monitoring centre for drugs and drug addiction (EMCDDA). European drug report: trends and developments. Publications Office of the European Union, 2022.
    1. Reuter P, Pardo B. Can new psychoactive substances be regulated effectively? An assessment of the British Psychoactive Substances Bill. Addiction. 2017;112:25–31. - DOI - PubMed
    1. Shafi A, Berry AJ, Sumnall H, Wood DM, Tracy DK. New psychoactive substances: a review and updates. Ther Adv Psychopharmacol. 2020;10:2045125320967197. - DOI - PMC - PubMed
    1. Soussan C, Kjellgren A. The users of novel psychoactive substances: online survey about their characteristics, attitudes and motivations. Int J Drug Policy. 2016;32:77–84. - DOI - PubMed

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