The ongoing psychedelic renaissance has prompted a renewed search for novel drugs based on modifying existing psychedelic motifs. In this study, a synthesis of 4-bromo-N,N-dimethyltryptamine (4-Br-DMT) was achieved and used as a late-stage intermediate for analog development. Specifically, we were able to synthesize and access novel molecules by forming carbon–carbon bonds at the C4 position using palladium cross-coupling reactions. Using the synthetic route described here will facilitate the rapid development of a library of tryptamines with novel 4-position substitutions to investigate structure–activity relationships (SARs) with serotonergic targets. Furthermore, the pharmacological target profile and biological effects of 4-Br-DMT were compared to the 4-hydroxy-N,N-dimethyltryptamine (psilocin) and nonring-substituted analog, N,N-dimethyltryptamine (DMT). Overall, the data indicate that 4-Br-DMT has a serotonergic profile without psychedelic-like effects in mice but has a reduced safety profile compared to psilocin and DMT.

Tryptamine psychedelics induce psychoactive effects via agonist actions at serotonin 2A receptors (5-HT2A), but the compounds are generally nonselective. 4-Methoxy-N-methyl-N-isopropyltryptamine (4-MeO-MiPT) is a 5-HT2A agonist which also blocks the 5-HT transporter (SERT) and has blunted visual and other psychedelic effects in humans. Here, we compared the pharmacology of 4-MeO-MiPT, its 4-hydroxy derivative (4-HO-MiPT), and related analogs with N-alkyl or 4-alkoxy variations. We hypothesized that compounds with more potent SERT uptake inhibition would display reduced 5-HT2A-mediated psychedelic-like effects in the mouse head twitch response (HTR) model. In vitro target profiling revealed potent and efficacious 5-HT receptor activities for most of the compounds, including 5-HT2A receptor agonism (EC50 = 10–118 nM, Emax = 72–97% 5-HT). Importantly, 4-MeO-MiPT and its N,N-diisopropyl (4-MeO-DiPT) and N-methyl-N-cyclopropyl (4-MeO-McPT) analogs displayed more potent uptake inhibition at SERT (IC50 = 17–107 nM) than their 4-OH counterparts (IC50 = 280–423 nM). Studies administering the drugs subcutaneously to C57BL/6J mice revealed that 4-HO- and 4-MeO-MiPT (0.03–30 mg/kg) had similar potencies for inducing HTRs (ED50 = 0.75 vs 0.97 mg/kg), but 4-MeO-MiPT had reduced efficacy (Emax = 77 vs 34 HTRs/30 min). A similar trend for decreased HTRs was observed for 4-MeO-DiPT and 4-MeO-McPT. Pretreatment with the SERT inhibitor fluoxetine (10 mg/kg) prior to 4-HO-MiPT, 4-HO-DiPT, or 4-HO-McPT reduced the maximal number of HTRs to levels observed for their respective 4-MeO analogs. Overall, our data indicate that 4-MeO-MiPT interacts with 5-HT2A and other 5-HT receptors, but the drug also inhibits SERT to reduce the efficacy of psychedelic-like effects in mice. Therefore, 4-MeO-MiPT and other dual 5-HT2A/SERT ligands may be therapeutically relevant compounds with reduced potential for traditional acute psychedelic effects.

Tryptamine psychedelics induce psychoactive effects via agonist actions at serotonin 2A receptors (5-HT2A), but the compounds are generally nonselective. 4-Methoxy-N-methyl-N-isopropyltryptamine (4-Me...

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Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-,-dimethyltryptamine Analogs in Mice

Rationale The head twitch response (HTR) is a spontaneously occurring behavior in mice that is increased in frequency by serotonergic psychedelics. The mouse HTR is often used as a proxy for psychedel...

Serotonergic psychedelics induce the head twitch response (HTR) in mice, an index of serotonin (5-HT) 2A receptor (5-HT2A) agonism and a behavioral proxy for psychedelic effects in humans. Existing me...

Abstract. Identification of N,N-dimethylpentylone (DMP) in counterfeit “Ecstasy” and “Molly” tablets poses risk to public health due to its adverse effects

This brief review highlights some of the structure–activity relationships of classic serotonergic psychedelics. In particular, we discuss structural features of three chemotypes: phenethylamines, erg...

In a quiet courtroom housed on the second floor of the Drug Enforcement Agency’s (DEA) Museum and Visitors Center in Arlington, Virginia, a legal battle is unfolding over the status of two key…

2-Benzylbenzimidazole derivatives or ‘nitazenes’ are increasingly present on the recreational drug market. Here, we report the synthesis and pharmacol…

LSD itself, then, is not a natural product. And neither is the compound to the right of it - that's lisuride, which was synthesized in the early 1960s. A lot of work has been done on this chemical framework, and lisuride itself has been marketed as a drug over the years for migraine and several other indications. It has no hallucinogenic effects, though.

LSD itself, then, is not a natural product. And neither is the compound to the right of it - that's lisuride, which was synthesized in the early 1960s. A lot of work has been done on this chemical framework, and lisuride itself has been marketed as a drug over the years for migraine and several other indications. It has no hallucinogenic effects, though.

Molecular Psychiatry - Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone

His work with psychedelic and mood-altering drugs generated immense scientific interest, helped patients suffering with depression and addiction