Serotonin Transporter Blockade Reduces the Psychedelic-Like Effects of 4-Methoxy- <i>N</i> -methyl- <i>N</i> -isopropyltryptamine and Related Analogs

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.