Chemistry:6-Fluoro-DET

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6-Fluoro-DET, or 6-F-DET, also known as 6-fluoro-N,N-diethyltryptamine, is a substituted tryptamine derivative related to psychedelic drugs such as diethyltryptamine (DET).[1]

Use and effects

6-Fluoro-DET produces physiological effects but does not produce hallucinogenic effects in humans.[1]

Pharmacology

Pharmacodynamics

6-Fluoro-DET acts as a partial agonist at the serotonin 5-HT2A receptor,[2] but while it produces similar physiological effects to psychedelics, it does not appear to produce psychedelic effects itself even at high doses. Relatedly, 6-F-DET does not substitute for LSD in drug discrimination tests and does not produce the head-twitch response in rodents.[2][3][4] For the preceding reasons, it saw some use as an active placebo in early clinical trials of psychedelic drugs, but was regarded as having little use otherwise,[5] though more recent research into compounds such as AL-34662, tabernanthalog, and zalsupindole has shown that these kind of non-psychedelic serotonin 5-HT2A agonists can have various useful applications.[6][7][8][9][10][11]

A hypothesis for the lack of head-twitch response in mice and hallucinogenic effects in humans is that 6-F-DET acts as a 5-HT2A receptor partial agonist of the Gq signaling pathway.[2] This hypothesis explains the lack of hallucinogenic effects of other 5-HT2A receptor ligands, which are also weak Gq agonists and below the efficacy threshold found to induce psychedelic effects, like 25N-N1-Nap, 2-Br-LSD, lisuride, tabernanthalog, and 6-MeO-DMT.[2][10][12]

Chemistry

Analogues

Analogues of 6-fluoro-DET include 6-fluoro-DMT, 5-fluoro-DMT, 5-chloro-DMT, 5-bromo-DMT, 5-fluoro-AMT, 6-fluoro-AMT, 6-methyl-DMT, 6-MeO-DMT, 6-hydroxy-DMT, and bretisilocin (5-fluoro-MET), among others.

History

6-Fluoro-DET was first described in the scientific literature by Stephen Szara and colleagues by 1963.[13]

See also

References

  1. ↑ 1.0 1.1 Shulgin, Alexander; Shulgin, Ann (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN 0-9630096-9-9. OCLC 38503252. http://www.erowid.org/library/books_online/tihkal/tihkal.shtml. 
  2. ↑ 2.0 2.1 2.2 2.3 "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential". Nature Communications 14 (1): 8221. 2023. doi:10.1038/s41467-023-43904-4. PMID 38001451. 
  3. ↑ "Psychedelic-Inspired Medium-Throughput Assays for the Development of Next-Generation Neurotherapeutics". https://www.proquest.com/openview/556de98980d27bfee6bd3cdef6d94fe0/. "6-F-DMT has been thought to be non-hallucinogenic as 6-F-DET (6-fluoro-N,N-diethyltryptamine) has been shown to not substitute for LSD in DD." 
  4. ↑ "Fluorinated tryptamine compounds, analogues thereof, and methods using same". 2 June 2022. https://patents.google.com/patent/WO2022256554A1/. 
  5. ↑ "Clinical evaluation of some hallucinogenic tryptamine derivatives". The Journal of Nervous and Mental Disease 145 (4): 306–313. October 1967. doi:10.1097/00005053-196710000-00005. PMID 6076017. 
  6. ↑ "Pharmacology and Classification of LSD-like Hallucinogens". Drug Addiction II. Handbuch der experimentellen Pharmakologie. Handbook of Experimental Pharmacology. 45. Berlin, Heidelberg: Springer. 1977. pp. 305–368. doi:10.1007/978-3-642-66709-1_3. ISBN 978-3-642-66711-4. 
  7. ↑ "Effect of ring fluorination on the pharmacology of hallucinogenic tryptamines". Journal of Medicinal Chemistry 43 (24): 4701–4710. November 2000. doi:10.1021/jm000339w. PMID 11101361. 
  8. ↑ "5-HT2A receptor-stimulated phosphoinositide hydrolysis in the stimulus effects of hallucinogens". Pharmacology, Biochemistry, and Behavior 72 (1–2): 29–37. May 2002. doi:10.1016/s0091-3057(01)00720-1. PMID 11900766. 
  9. ↑ Chemistry and Structure-Activity Relationships of Psychedelics. Current Topics in Behavioral Neurosciences. 36. 2018. pp. 1–43. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. 
  10. ↑ 10.0 10.1 "A non-hallucinogenic psychedelic analogue with therapeutic potential". Nature 589 (7842): 474–479. 2021. doi:10.1038/s41586-020-3008-z. PMID 33299186. 
  11. ↑ "Psychedelic-inspired drug discovery using an engineered biosensor". Cell 184 (10): 2779–2792.e18. May 2021. doi:10.1016/j.cell.2021.03.043. PMID 33915107. 
  12. ↑ "Comparative pharmacological effects of lisuride and lysergic acid diethylamide revisited". ACS Pharmacology & Translational Science 7 (3): 641–653. 2024. doi:10.1021/acsptsci.3c00274. 
  13. ↑ "Synthesis and pharmacological activity of fluorinated tryptamine derivatives". J Med Chem 6: 716–719. November 1963. doi:10.1021/jm00342a019. PMID 14184932. 



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