6-Fluoro-DMT

Last updated

6-Fluoro-DMT
6-Fluoro-DMT skeletal.svg
6-Fluoro-DMT 3D.png
Clinical data
Other names6-Fluoro-N,N-dimethyltryptamine; 6-Fluoro-DMT; 6-F-DMT; 6F-DMT
Drug class Serotonin receptor modulator; Serotonin 5-HT2A receptor agonist
ATC code
  • None
Identifiers
  • 2-(6-fluoro-1H-indol-3-yl)-N,N-dimethyl-ethanamine
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C12H15FN2
Molar mass 206.264 g·mol−1
3D model (JSmol)
  • CN(CCC1=CNC2=C1C=CC(F)=C2)C
  • InChI=1S/C12H15FN2/c1-15(2)6-5-9-8-14-12-7-10(13)3-4-11(9)12/h3-4,7-8,14H,5-6H2,1-2H3 Yes check.svgY
  • Key:DZXZPVGWRZCXDH-UHFFFAOYSA-N Yes check.svgY
   (verify)

6-Fluoro-DMT, also known as 6-fluoro-N,N-dimethyltryptamine, is a serotonin receptor modulator of the tryptamine family related to dimethyltryptamine (DMT). [1] [2]

Contents

Use and effects

6-Fluoro-DMT was not included nor mentioned in Alexander Shulgin's book TiHKAL (Tryptamines I Have Known and Loved). [3] However, he did briefly discuss it in an early literature review, but its properties and effects in humans were not described. [1]

The closely related compound 6-fluoro-DET has been found to be inactive in terms of psychedelic-type effects both in animals and humans. [4] [5] [6] [3] [7] Relatedly, it has been claimed that 6-fluoro-DMT is inactive as a psychedelic similarly to 6-fluoro-DET, though it is unclear whether this claim was based on actual testing or on extrapolation from 6-fluoro-DET and theoretical notions. [8] In the 1960s, it had been theorized by Stephen Szára and colleagues that psychedelic tryptamines were prodrugs that required 6-hydroxylation to become hallucinogenic, but this theory was later found to be incorrect. [9] [10] [11] [12] Indeed, the related compound 6-fluoro-AMT is known to be robustly active as a psychedelic. [13] [14]

Pharmacology

Pharmacodynamics

6-Fluoro-DMT activities
Target Affinity (Ki, nM)
5-HT1A 693–865 (Ki)
IA (EC50 Tooltip half-maximal effective concentration)
5-HT1B 218
5-HT1D 55
5-HT1E 461
5-HT1F ND
5-HT2A 511–866 (Ki)
41–16,830 (EC50)
74% (Emax Tooltip maximal efficacy)
5-HT2B 30
5-HT2C 674 (Ki)
1.252–5.816 (EC50)
105–131% (Emax)
5-HT3 >10,000
5-HT4 ND
5-HT5A 961
5-HT6 26
5-HT7 41
α1A 173
α1B >10,000
α1D ND
α2A >10,000
α2B 260
α2C 149
β1 >10,000
β2 >10,000
β3 ND
D1 547
D2 610
D3 867
D4 1,454
D5 6,291
H1 47
H2 925
H3, H4 >10,000
M1–M5 >10,000
I1 898
σ1 6,892
σ2 7,128
TAAR1 Tooltip Trace amine-associated receptor 1ND
SERT Tooltip Serotonin transporter145 (Ki)
NET Tooltip Norepinephrine transporter>10,000 (Ki)
DAT Tooltip Dopamine transporter>10,000 (Ki)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [15] [2] [16] [17]

6-Fluoro-DMT is known to possess varying affinities for serotonin receptors, adrenergic receptors, dopamine receptors, histamine receptors, the imidazoline I1 receptor, sigma receptors, and the serotonin transporter (SERT). [2] It has been found to be a potent partial agonist of the serotonin 5-HT2A receptor and a potent full agonist of the serotonin 5-HT2C receptor. [2] In another study however, it showed affinity for the serotonin 5-HT1A and 5-HT2A receptors but was inactive as a serotonin 5-HT1A receptor agonist and showed low potency as a serotonin 5-HT2A receptor agonist. [16] [17] On the other hand, it was only about 3-fold less potent than dimethyltryptamine (DMT) as a serotonin 5-HT2A receptor agonist in this study. [17] 6-Fluoro-DMT is less active than dimethyltryptamine (DMT) in producing effects in animal studies. [1] [18]

Chemistry

Analogues

Analogues of 6-fluoro-DMT include 4-fluoro-DMT, 5-fluoro-DMT, 5-fluoro-AMT, 5-bromo-DMT, 5-chloro-DMT, bretisilocin (5-fluoro-MET), 6-fluoro-AMT, and 6-fluoro-DET, among others.

History

6-Fluoro-DMT was first described in the scientific literature by at least 1966. [1] [18] [8]

See also

References

  1. 1 2 3 4 Shulgin AT (1976). "Psychotomimetic Agents". In Gordon M (ed.). Psychopharmacological Agents: Use, Misuse and Abuse. Medicinal Chemistry: A Series of Monographs. Vol. 4. Academic Press. pp. 59–146. doi:10.1016/b978-0-12-290559-9.50011-9. ISBN   978-0-12-290559-9. This metabolically available site (6 position) was blocked with a fluoro-group in a number of these N,N-dialkyltryptamines. 6-Fluoro-N,N-dimethyltryptamine [(XXXVI), R = CH3] was again found to be less active than the parent N,N-dimethyltryptamine in animal studies (Kalir and Szara, 1966). However, clinical studies with the ethyl homolog [(XXXVI), R = C2H5] has shown that it produces most of the somatic effects of the comparison drug N,N-dipropyltryptamine without any of the psychological changes. It is proposed as an "active placebo" in controlling experiments with possible hallucinogenics (Faillace et al., 1967). The present evidence indicates that chemical substitution on the 6 position of the tryptamine system destroys the psychotomimetic potential of the compound.
  2. 1 2 3 4 Ray TS (February 2010). "Psychedelics and the human receptorome". PLOS ONE. 5 (2) e9019. Bibcode:2010PLoSO...5.9019R. doi: 10.1371/journal.pone.0009019 . PMC   2814854 . PMID   20126400.
  3. 1 2 Shulgin A, Shulgin A (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN   0-9630096-9-9. OCLC   38503252.
  4. ↑ Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, et al. (2023). "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential". Nature Communications. 14 (1): 8221. doi: 10.1186/s12969-023-00927-3 . PMC   10694965 . PMID   38001451.
  5. ↑ "Psychedelic-Inspired Medium-Throughput Assays for the Development of Next-Generation Neurotherapeutics". ProQuest. 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.
  6. ↑ "Fluorinated tryptamine compounds, analogues thereof, and methods using same". Google Patents. 2 June 2022. Retrieved 8 April 2025.
  7. ↑ Faillace LA, Vourlekis A, Szara S (October 1967). "Clinical evaluation of some hallucinogenic tryptamine derivatives". J Nerv Ment Dis. 145 (4): 306–313. doi:10.1097/00005053-196710000-00005. PMID   6076017.
  8. 1 2 Kline TB (1980). Structure-Activity Relationships Of N,N-Dialkyltryptamines Substituted In The Benzene Moiety. All ETDs from UAB (Ph.D. thesis). University of Alabama at Birmingham. Retrieved 15 November 2024– via UAB Digital Commons. Neither 6-hydroxy DMT, 5-methoxy-6-hydroxy DMT, nor the metabolically blocked 6-fluoro DMT are active hallucinogens in man.
  9. ↑ Szara S, Hearst E (1962). "The 6-Hydroxylation of Tryptamine Derivatives: A Way of Producing Psychoactive Metabolites" . Annals of the New York Academy of Sciences. 96 (1): 134–141. Bibcode:1962NYASA..96..134S. doi:10.1111/j.1749-6632.1962.tb50108.x. ISSN   0077-8923 . Retrieved 8 April 2025.
  10. ↑ Szara S, Hearst E, Putney F (1962). "Metabolism and behavioural action of psychotropic tryptamine homologues" . International Journal of Neuropharmacology. 1 (1–3): 111–117. doi:10.1016/0028-3908(62)90015-1 . Retrieved 8 April 2025.
  11. ↑ Szara S, Rockland LH, Rosenthal D, Handlon JH (September 1966). "Psychological effects and metabolism of N,N-diethyltryptamine in man". Arch Gen Psychiatry. 15 (3): 320–329. doi:10.1001/archpsyc.1966.01730150096014. PMID   5330062.
  12. ↑ Taborsky RG, Delvigs P, Page IH (August 1966). "6-hydroxylation: effect on the psychotropic potency of tryptamines". Science. 153 (3739): 1018–1020. Bibcode:1966Sci...153.1018T. doi:10.1126/science.153.3739.1018. PMID   5917552.
  13. ↑ Morris H (2010). "Life is a Cosmic Giggle on the Breath of the Universe. A Tour of Gordon Todd Skinner's Subterranean LSD Palace". Vice Magazine. Archived from the original on 2014-10-13. Retrieved 2017-08-23.{{cite web}}: CS1 maint: overridden setting (link)
  14. ↑ "Unusual Analogues: Drugs Used by Gordon Todd Skinner". thislandpress.com. This Land Press. Archived from the original on 17 April 2016. Retrieved 8 April 2016.
  15. ↑ "Kᵢ Database". PDSP. 22 March 2025. Retrieved 22 March 2025.
  16. 1 2 Chen X, Li J, Yu L, Maule F, Chang L, Gallant JA, et al. (October 2023). "A cane toad (Rhinella marina) N-methyltransferase converts primary indolethylamines to tertiary psychedelic amines". J Biol Chem. 299 (10) 105231. doi: 10.1016/j.jbc.2023.105231 . PMC   10570959 . PMID   37690691.
  17. 1 2 3 Chen X, Li J, Yu L, Dhananjaya D, Maule F, Cook S, et al. (10 March 2023), Bioproduction platform using a novel cane toad (Rhinella marina) N-methyltransferase for psychedelic-inspired drug discovery (PDF), doi: 10.21203/rs.3.rs-2667175/v1 , retrieved 18 March 2025
  18. 1 2 Kalir A, Szara S (May 1966). "Synthesis and pharmacological activity of alkylated tryptamines" (PDF). J Med Chem. 9 (3): 341–344. doi:10.1021/jm00321a017. PMID   5960901.
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