Serotonin Transporter Blockade Reduces the Psychedelic-Like Effects of 4-Methoxy-<i>N</i>-methyl-<i>N</i>-isopropyltryptamine and Related Analogs.
Abstract
Tryptamine psychedelics induce psychoactive effects via agonist actions at serotonin 2A receptors (5-HT<sub>2A</sub>), but the compounds are generally nonselective. 4-Methoxy-<i>N</i>-methyl-<i>N</i>-isopropyltryptamine (4-MeO-MiPT) is a 5-HT<sub>2A</sub> 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 <i>N-</i>alkyl or 4-alkoxy variations. We hypothesized that compounds with more potent SERT uptake inhibition would display reduced 5-HT<sub>2A</sub>-mediated psychedelic-like effects in the mouse head twitch response (HTR) model. <i>In vitro</i> target profiling revealed potent and efficacious 5-HT receptor activities for most of the compounds, including 5-HT<sub>2A</sub> receptor agonism (EC<sub>50</sub> = 10-118 nM, <i>E</i><sub>max</sub> = 72-97% 5-HT). Importantly, 4-MeO-MiPT and its <i>N</i>,<i>N</i>-diisopropyl (4-MeO-DiPT) and <i>N</i>-methyl-<i>N</i>-cyclopropyl (4-MeO-McPT) analogs displayed more potent uptake inhibition at SERT (IC<sub>50</sub> = 17-107 nM) than their 4-OH counterparts (IC<sub>50</sub> = 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 (ED<sub>50</sub> = 0.75 vs 0.97 mg/kg), but 4-MeO-MiPT had reduced efficacy (<i>E</i><sub>max</sub> = 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-HT<sub>2A</sub> 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-HT<sub>2A</sub>/SERT ligands may be therapeutically relevant compounds with reduced potential for traditional acute psychedelic effects.
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