4-Fluoro-DMT

{{Infobox drug

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| image = 4-Fluoro-dimethyltryptamine.svg

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| class = Serotonin 5-HT_2C receptor agonist

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| CAS_number = 1644-64-0

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| PubChem = 11492162

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| ChemSpiderID = 9666968

| UNII = A2FA8F63VS

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| ChEMBL = 197646

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| synonyms = 4-Fluoro-N,N-dimethyltryptamine; 4-F-DMT; 4F-DMT

| IUPAC_name = 2-(4-fluoro-1H-indol-3-yl)-N,N-dimethylethanamine

| C=12 | H=15 | F=1 | N=2

| SMILES = CN(C)CCC1=CNC2=C1C(=CC=C2)F

| StdInChI = 1S/C12H15FN2/c1-15(2)7-6-9-8-14-11-5-3-4-10(13)12(9)11/h3-5,8,14H,6-7H2,1-2H3

| StdInChIKey = ISJZKVWGUWBUFG-UHFFFAOYSA-N

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4-Fluoro-DMT (or 4-F-DMT), also known as 4-fluoro-N,N-dimethyltryptamine, is a serotonin receptor agonist of the tryptamine family and a close analogue of psilocin (4-HO-DMT) and dimethyltryptamine (DMT).{{cite web | vauthors = Blair JB | title=Synthesis and pharmacological evaluation of fluorinated hallucinogenic tryptamine analogs and thienopyrrole bioisosteres of N,N-dimethyltryptamine | website=Purdue e-Pubs | date=August 1997 | url=https://docs.lib.purdue.edu/dissertations/AAI9818919/ | access-date=20 March 2025}}{{cite journal | vauthors = Sard H, Kumaran G, Morency C, Roth BL, Toth BA, He P, Shuster L | title = SAR of psilocybin analogs: discovery of a selective 5-HT 2C agonist | journal = Bioorganic & Medicinal Chemistry Letters | volume = 15 | issue = 20 | pages = 4555–4559 | date = October 2005 | pmid = 16061378 | doi = 10.1016/j.bmcl.2005.06.104 }}{{cite journal | vauthors = Bentov M, Pelchowicz Z, Levy A | title=4-Fluoroindole and Derivatives | journal=Israel Journal of Chemistry | volume=2 | issue=1 | date=1964 | issn=0021-2148 | doi=10.1002/ijch.196400006 | pages=25–28}} It is a modestly selective serotonin 5-HT_2C receptor full agonist and doesn't appear to produce psychedelic-like effects in animals but instead produces antiobsessional-like effects.

Pharmacology

The drug's affinity (K_i) for the serotonin 5-HT_1A receptor was 135{{nbsp}}nM. This can be compared to psilocin's affinity of 378{{nbsp}}nM and serotonin's affinity of 1.7{{nbsp}}nM. In another study, 4-F-DMT showed affinities (K_i) of 335{{nbsp}}nM for the serotonin 5-HT_2A receptor, 8.39{{nbsp}}nM for the serotonin 5-HT_2B receptor, and 82–84{{nbsp}}nM for the serotonin 5-HT_2C receptor. Its activational potencies ({{Abbrlink|EC₅₀|half-maximal effective concentration}}) and efficacies ({{Abbrlink|E_max|maximal efficacy}}) were 949{{nbsp}}nM (49%) at the serotonin 5-HT_2A receptor, 1,180{{nbsp}}nM (38%) at the serotonin 5-HT_2B receptor, and 99{{nbsp}}nM (93%) at the serotonin 5-HT_2C receptor. 4-F-DMT showed dramatically less potent {{Abbr|EC₅₀|half-maximal effective concentration}} values at the serotonin 5-HT_2A and 5-HT_2B receptors compared to psilocin (40- and 20-fold less potent), whereas its potency was less markedly reduced at the serotonin 5-HT_2C receptor (about 3-fold less potent). Hence, whereas psilocin is a balanced agonist of the serotonin 5-HT₂ receptors, 4-F-DMT is a selective serotonin 5-HT_2C receptor agonist with about 10-fold preference for activation of this receptor over the serotonin 5-HT_2A and 5-HT_2B receptors. Moreover, whereas psilocin was a partial agonist of the serotonin 5-HT_2C receptor ({{Abbr|E_max|maximal efficacy}} = 51%), 4-F-DMT had higher efficacy and was a full agonist ({{Abbr|E_max|maximal efficacy}} = 93%).

4-F-DMT produced partial generalization (0–56%) to LSD in animal drug discrimination tests, but this was not statistically significant and an {{Abbrlink|ED₅₀|median effective dose}} was not calculated. It also failed to substitute for DOI in drug discrimination tests (10–33%). Conversely, psilocin produced full generalization at much lower doses. Hence, 4-F-DMT may not be hallucinogenic in humans. On the other hand, the drug was dose-dependently and strongly active in producing antiobsessional-like effects in an animal model of obsessive–compulsive disorder (OCD) (specifically inhibition of serotonin-induced scratching behavior), an effect that it is thought may be mediated by serotonin 5-HT_2C receptor agonism.

Chemistry

4-F-DMT is more lipophilic than psilocin (4-HO-DMT) due to lacking its hydrophilic hydroxyl group, and hence 4-F-DMT might cross the blood–brain barrier more readily than psilocin.

Derivatives of 4-F-DMT such as 4-fluoro-5-methoxy-DMT (4-F-5-MeO-DMT) have also been synthesized and studied.{{cite journal | vauthors = Blair JB, Kurrasch-Orbaugh D, Marona-Lewicka D, Cumbay MG, Watts VJ, Barker EL, Nichols DE | title = Effect of ring fluorination on the pharmacology of hallucinogenic tryptamines | journal = Journal of Medicinal Chemistry | volume = 43 | issue = 24 | pages = 4701–4710 | date = November 2000 | pmid = 11101361 | doi = 10.1021/jm000339w }}