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

  • ACS Chem Neurosci. 2026 Jun 17;17(12):2348-2363. doi: 10.1021/acschemneuro.6c00083.
Grant C Glatfelter  1 ,  Serena S Schalk  2 ,  Donna Walther  1 ,  Alexander D Maitland  1 ,  Nicholas R Gonzalez  1 ,  John S Partilla  1 ,  Nicholas A Anas  3 ,  Andrew R Chadeayne  3 ,  Marilyn Naeem  4 ,  David R Manke  4 ,  John D McCorvy  2  5  6 ,  Michael H Baumann  1
Affiliations
  • 1. Designer Drug Research Unit, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224, United States.
  • 2. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
  • 3. CaaMTech, Inc., Issaquah, Washington 98027, United States.
  • 4. Department of Chemistry & Biochemistry, University of Massachusetts Dartmouth, North Dartmouth, Massachusetts 02747, United States.
  • 5. Department of Pharmacology and Toxicology, Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
  • 6. Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
PMID: 42200433 DOI: 10.1021/acschemneuro.6c00083
Abstract

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.

Keywords
4-MeO-MiPT; 5-HT2A; SERT; head twitch response; mice; psychedelics.
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