Monday, 21 September 2026

Blixeprodil

 

Blixeprodil

CAS 2881017-49-6

MF C13H16FNO MW 221.27 g/mol

Cyclohexanone, 2-(4-fluorophenyl)-2-(methylamino)-, (2R)-

(2R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one
N-methyl-D-aspartate (NMDA) receptor antagonist, GM-1020, GM1020, (R)-4-Fluorodeschloroketamine, (R)-4-FDCK, (R)-4FDCK, S2MGG2PC5K

Blixeprodil,[5] also known by its developmental code name GM-1020 or as (R)-4-fluorodeschloroketamine ((R)-4-FDCK), is an NMDA receptor antagonist related to ketamine which is under development for the treatment of major depressive disorder, bipolar depression, and other depressive disorders.[1][6][2][3][7][8] It is taken by mouth.[1][2][3]

The drug is orally active, in contrast to the poor oral bioavailability of ketamine.[3] Its oral bioavailability is >60%.[4][9] The time to peak levels of blixeprodil is 1.5 hours and its elimination half-life is 4.3 hours.[4] In a clinical study comparing it with the serotonergic psychedelic bretisilocin (GM-2505), both blixeprodil and bretisilocin produced hallucinogenic effects.[10]

Blixeprodil shows antidepressant-like effects in rodents.[3][11][4][9] It appears to have a greater separation between antidepressant-like and ataxia-inducing doses than ketamine in rodents and hence might have better tolerability.[3][7][9] Whereas ketamine shows only 3-fold separation between antidepressant-like and ataxic doses, there was 13-fold separation for blixeprodil, and it did not produce hyperlocomotion at doses >20-fold higher than the minimum antidepressant-like dose.[9] In relation to the preceding, blixeprodil is claimed to be non-dissociative at therapeutic doses.[2][4] However, dissociative and other related effects have been observed at low incidences and at higher doses.[4]

The drug is a close analogue of ketamine, with a 4-fluoro group instead of a 2-chloro group on the phenyl ring and in (2R)-enantiopure form.[12] Hence, blixeprodil is related to arketamine ((R)-ketamine); it is said to "bet" on the notion that arketamine is importantly involved in the antidepressant effects of ketamine, in spite of arketamine having less propensity for inducing dissociation.[13]

Blixeprodil is being developed by Gilgamesh Pharmaceuticals.[1][6][2] As of July 2024, it is in phase 2 clinical trials for major depressive disorder and bipolar depression and is in phase 1 trials for other depressive disorders.[1][6][2]

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021134086&_cid=P12-MNWKJX-24279-1

Example 15: Preparation of Compounds 117rac and 18rac

Step 1: Preparation of 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one

[0364] A mixture of 2-(4-fluorophenyl)cyclohexan-1-one (5 g, 26.01 mmol, 1 eq), ceric ammonium nitrate (CAN, 28.52 g, 52.02 mmol, 2 eq), and Cu(OAc)2 (945 mg, 5.20 mmol, 0.2 eq) in DCE (50 mL) was stirred at 85 °C for 12 hrs. The mixture was cooled, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 0/1) to afford 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one (2.5 g, 10.54 mmol, 40.52% yield) as a yellow oil.1H NMR (400MHz, CHLOROFORM-d) δ = 7.47 - 7.29 (m, 2H), 7.22 - 7.04 (m, 2H), 3.12 (ddd, J = 3.6, 10.0, 14.0 Hz, 1H), 2.86 - 2.76 (m, 1H), 2.75 - 2.62 (m, 1H), 2.61 - 2.47 (m, 1H), 2.08 - 1.86 (m, 3H), 1.80 (dt, J = 3.6, 9.2 Hz, 1H).

Step 2: Preparation of 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (117rac)

[0365] A mixture of 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one (3 g, 12.65 mmol, 1 eq) and Zn (19.85 g, 303.51 mmol, 24 eq) in AcOH (25 mL) was stirred at 20 °C for 12 hrs. The mixture was cooled, filtered, and concentrated. The residue was dissolved in DCM, washed with sat.

NaHCO3, H2O, and brine, dried over Na2SO4, filtered, and concentrated. The residue was

purified by silica gel (PE:EA = 50:1 - 8:1) to afford 2-amino-2-(4-fluorophenyl)cyclohexan-1- one (1.5 g, 7.24 mmol, 57.23% yield) (117rac) as a brown oil. LCMS (RT = 1.336 min, MS calc.: 207.11, [M+H]+ = 208.1) 1H NMR (400MHz, CHLOROFORM-d) δ = 7.26 - 7.19 (m, 2H), 7.11 - 7.01 (m, 2H), 2.87 - 2.73 (m, 1H), 2.50 - 2.42 (m, 1H), 2.41 - 2.29 (m, 1H), 2.04 - 1.96 (m, 1H), 1.93 (s, 2H), 1.83 - 1.63 (m, 4H); 3C NMR (101 MHz, CHLOROFORM-d) δ = 213.28, 163.27, 160.82, 137.67, 137.63, 127.99, 127.91, 116.16, 115.95, 65.93, 39.71, 28.08, 22.61

Step 3: Preparation of 2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one (18rac)

[0366] A mixture of 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (1.3 g, 6.27 mmol, 1 eq) and methyl trifluoromethanesulfonate (1.03 g, 6.27 mmol, 1 eq) in hexafluoroisopropanol (HFIP, 130 mL) was stirred at 0 - 25 °C for 12 hrs under N2 atmosphere. The mixture was filtered and concentrated. The residue was adjusted to pH = 7 with sat. Na2CO3 (20 ml). The aqueous phase was extracted with EA (50 mL x 2). The combined organic phase was washed with brine (50 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (column: Welch Xtimate C18250*70 mm, 10 μm; mobile phase: A: water(0.05% NH3H2O), B: ACN; B%: 18% - 48%, 32 min) to afford 2-(4-fluorophenyl)-2- (methylamino)cyclohexan-1-one (590 mg, 4.02 mmol, 42.45% yield) (18rac) as a white solid. LCMS (RT = 1.415 min, MS calc.: 221.12, [M+H]+ = 222.1); 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.26 - 7.17 (m, 2H), 7.07 (br t, J = 8.4 Hz, 2H), 2.92 - 2.74 (m, 1H), 2.50 - 2.26 (m, 3H), 2.12 - 1.93 (m, 4H), 1.90 - 1.63 (m, 4H); 13C NMR (101 MHz, CHLOROFORM-d) δ = 211.15, 163.20, 160.75, 134.68, 134.65, 128.99, 128.91, 115.79, 115.58, 69.37, 39.70, 35.85, 28.87, 27.70, 22.21.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022272174&_cid=P12-MNWKJX-24279-1

Example 1: Preparation of Compounds 1 and 2 and Their Enantiomers.

Step 1: Preparation of 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one

[0110] A mixture of 2-(4-fluorophenyl)cyclohexan-1-one (14 g, 72.83 mmol, 1 eq), CAN (79.85 g, 145.66 mmol, 72.59 mL, 2 eq), and Cu(OAc)2 (2.65 g, 14.57 mmol, 0.2 eq) in DCE (140 mL) was stirred at 85 °C for 12 h. On completion, the mixture was filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 0/1) to afford 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one (6.1 g, 25.71 mmol, 35.31% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.41 - 7.31 (m, 2H), 7.16 (t, J=8.4 Hz, 2H), 3.11 (ddd, J=3.6, 10.4, 14.0 Hz, 1H), 2.87 - 2.76 (m, 1H), 2.73 - 2.64 (m, 1H), 2.60 -2.48 (m, 1H), 2.02 - 1.88 (m, 3H), 1.84 - 1.72 (m, 1H).

Step 2: Preparation of 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (1)

[0111] To a mixture of 2-(4-fluorophenyl)-2-nitrocyclohexan-1-one (5.6 g, 23.61 mmol, 1 eq) in AcOH (10 mL) was added Zn (15.44 g, 236.06 mmol, 10 eq) in several portions and the resulting mixture was stirred at 30 °C for 12 h. On completion, the mixture was filtered and concentrated. The residue was dissolved in DCM (20 mL), washed with sat. aq. NaHCO3 (10 mL), H2O (5 mL), and brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by prep-HPLC (column: Agela DuraShell C18 (250 mm*80 mm, 10 μm); mobile phase: A: water (NH4HCO3), B: ACN; B%: 35%, 20 min) to afford 2-amino-2-(4-fluorophenyl)cyclohexan-1-one (2.9 g, 13.99 mmol, 59.28% yield, 1) as a brown oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.52 - 7.40 (m, 2H), 7.32 (br s, 1H), 7.34 - 7.20 (m, 2H), 2.93 - 2.92 (m, 1H), 3.08 - 2.92 (m, 1H), 2.74 - 2.63 (m, 1H), 2.63 - 2.50 (m, 1H), 2.28 - 2.16 (m, 1H), 2.10 (br s, 2H), 2.04 - 1.85 (m, 4H).

Note: The free base of this compound is unstable and dimerizes over time. It should be stored frozen or quickly converted to the HCl salt to prevent this.

Step 3: Preparation of (S)-2-amino-2-(4-fluorophenyl)cyclohexan-1-one (1S) and (R)-2-amino-2-(4-fluorophenyl)cyclohexan-1-one (1R)

[0112] The racemate 1 (2.9 g) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: CO2, B: 0.1% NH3H2O in ETOH; B%: 27%, multi-injection process with 6-min spacing between injections) to afford ENT-1 free base (RT = 2.266 min, 1.1 g, 1.62 mmol, 1S_FB) as a yellow oil and ENT-2 free base (RT = 2.945 min, 1.1 g, 1.28 mmol, 1R_FB) as a yellow oil.

[0113] A portion of each free base was further purified by prep-HPLC (column: Welch Xtimate C18 (100 mm*25 mm, 3 μm); mobile phase: A: water (0.04% HCl), B: ACN; B%: 1% - 20%, 8 min) to afford ENT-1 HCl (RT = 2.266 min, 272 mg, HCl salt, 1S) as a white solid and ENT-2 HCl (RT = 2.945 min, 283 mg, HCl salt, 1R) as a white solid.

[0114] ENT-1 HCl, RT = 2.266 min (assigned here as the S isomer, 1S); LCMS (RT = 1.449 min, MS calc.: 207.1, [M+H]+ = 208.1); 1H NMR (400MHz, DMSO-d6) δ = 8.83 (br s, 3H), 7.50 - 7.42 (m, 2H), 7.41 - 7.32 (m, 2H), 3.03 (br dd, J=2.4, 14.0 Hz, 1H), 2.45 - 2.27 (m, 2H), 2.21 -2.05 (m, 1H), 1.97 (td, J=2.8, 9.6 Hz, 1H), 1.81 (br d, J=11.6 Hz, 1H), 1.71 - 1.47 (m, 2H); 13C NMR (101 MHz, DMSO-d6) δ = 206.52, 164.22, 161.76, 130.78, 130.69, 130.08, 130.05, 116.90, 116.68, 66.26, 34.75, 27.52, 21.53; ENT-2 HCl, RT = 2.945 min (assigned here as the R isomer, 1R); LCMS (RT = 1.449 min, MS calc.: 207.1, [M+H]+ = 208.0); 1H NMR (400MHz, DMSO-d6) δ = 8.84 (br s, 3H), 7.49 - 7.42 (m, 2H), 7.40 - 7.33 (m, 2H), 3.03 (br dd, J=1.6, 14.0 Hz, 1H), 2.45 - 2.27 (m, 2H), 2.23 - 2.06 (m, 1H), 1.97 (dt, J=2.8, 6.1 Hz, 1H), 1.81 (br d, J=11.6 Hz, 1H), 1.70 - 1.46 (m, 2H); 13C NMR (101 MHz, DMSO-d6) δ = 206.50, 164.22, 161.76, 130.78, 130.70, 130.08, 130.05, 116.89, 116.68, 66.26, 34.75, 27.51, 21.52.

[0115] The retention times above, which identify the enantiomers, were determined using the free bases using the following chiral analytical method: column: Chiralpak AD-3 (150 mm×4.6 mm I.D., 3 μm); mobile phase: A: CO2 B: EtOH (0.1% IPAm, v/v); gradient (Time (min)/A%/B%): 0.0/90/10, 0.5/90/10, 3.5/50/50, 4.5/50/50, 5.0/90/10; flow rate: 2.5 mL/min; column temp.: 35 °C; ABPR: 2,000 psi.

Step 4: Preparation of (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one (2S) and (R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one (2R)

[0116] Compound 1S_FB (540 mg, 2.61 mmol, 1 eq) and methyl trifluoromethanesulfonate (427.59 mg, 2.61 mmol, 285.06 μL, 1 eq) were combined in hexafluoroisopropanol (40 mL) at 0

°C under N2 atmosphere and then the mixture was allowed to warm to 25 °C and stirred for 12 h. On completion, the residue was adjusted to pH 7 with sat. aq. Na2CO3 (10 mL) and the combined organic phase was washed with brine (100 mL * 2), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge C18 (150 mm*50 mm, 10μm); mobile phase: A: water (10 mM NH4HCO3), B: ACN; B%: 30% - 50%, 10 min) to afford 2S (260 mg, 1.18 mmol, 45.10% yield) as a white solid. Compound 2R was prepared by the same procedure starting from 1R_FB (590 mg, 2.85 mmol) in hexafluoroisopropanol (60 mL) (other quantities scaled based on molar equivalents) and obtained as an off-white solid (260 mg, 1.18 mmol, 41.27% yield).

[0117] 2S (assigned here as the S isomer) (free base); LCMS (RT = 1.427 min, MS calc.: 221.1, [M+H]+ = 222.1); 1H NMR (400MHz, CHLOROFORM-d) δ = 7.21 (dd, J = 5.4, 8.8 Hz, 2H), 7.10 - 7.02 (m, 2H), 2.85 - 2.74 (m, 1H), 2.49 - 2.37 (m, 1H), 2.36 - 2.25 (m, 1H), 2.22 (br s, 1H), 2.03 (s, 3H), 1.96 (dt, J = 3.2, 5.8 Hz, 1H), 1.88 - 1.64 (m, 4H); 13C NMR (101 MHz, CHLOROFORM-d) δ = 211.25, 163.22, 160.76, 134.80, 134.77, 128.98, 128.90, 115.80, 115.59, 69.38, 39.73, 35.92, 28.92, 27.72, 22.24; 2R (assigned here as the R isomer) (free base); LCMS (RT = 1.415 min, MS calc.: 221.1, [M+H]+ = 222.1); 1H NMR (400MHz, CHLOROFORM-d) δ = 7.25 - 7.17 (m, 2H), 7.11 - 7.02 (m, 2H), 2.85 - 2.75 (m, 1H), 2.48 - 2.38 (m, 1H), 2.35 - 2.19 (m, 2H), 2.04 (s, 3H), 1.97 (br dd, J = 2.8, 6.1 Hz, 1H), 1.89 - 1.66 (m, 4H); 13C NMR (101 MHz, CHLOROFORM-d) δ = 211.24, 163.22, 160.77, 134.78, 134.74, 128.99, 128.91, 115.81, 115.60, 69.38, 39.73, 35.91, 28.91, 27.72, 22.24.

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References

References

  1.  "GM 1020". AdisInsight. 12 July 2024. Retrieved 20 February 2025.
  2.  Peplow M (June 2024). "Next-generation psychedelics: should new agents skip the trip?". Nature Biotechnology. 42 (6): 827–830. doi:10.1038/s41587-024-02285-1. PMID 38831049. Other companies are confident that they can further reduce or even erase those effects without losing therapeutic efficacy. Gilgamesh, for example, is taking that approach with ketamine, DMT and psilocybin. In the case of ketamine, says Kruegel, the dissociative side effects require that the subjects remain under supervision. So Gilgamesh designed a ketamine analog called GM-1020 that has no dissociative effects (distortions in sight, sound and feelings of detachment) and that also has better oral bioavailability than ketamine itself. After completing a phase 1 trial last year, the company began dosing patients with GM-1020 in a phase 2 trial for major depressive disorder in March. "The hope is that the psychoactive effects will be limited enough that this can eventually be taken at home," says Kruegel.
  3.  Klein AK, Austin EW, Cunningham MJ, Dvorak D, Gatti S, Hulls SK, et al. (May 2024). "GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents". Neuropsychopharmacology. 49 (6): 905–914. doi:10.1038/s41386-023-01783-1. PMC 11039472. PMID 38177696.
  4.  Marek G, Umbricht D, Christian E, Winters J, Raines S, Kiss L, et al. (December 2023). "ACNP 62nd Annual Meeting: Poster Abstracts P251 – P500: P352. GM-1020: An Oral NMDA Receptor Antagonist for Depression Demonstrates Target Engagement at Doses That Do Not Cause Dissociation, Ataxia or Sedation in a Phase 1 Single Ascending Dose Study". Neuropsychopharmacology. 48 (Suppl 1): 211–354 (269–269). doi:10.1038/s41386-023-01756-4. PMC 10729596. PMID 38040810.
  5.  https://iris.who.int/bitstream/handle/10665/380497/9789240107038-eng.pdf "blixeprodilum blixeprodil (2R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one N-methyl-D-aspartate (NMDA) receptor antagonist"
  6.  "Delving into the Latest Updates on GM-1020 with Synapse". Synapse. 15 February 2025. Retrieved 20 February 2025.
  7.  Klein A, Dvorak D, Austin E, Marek G, Sporn J, Hughes Z, et al. (2023). "531. GM-1020 is a Novel, Orally Bioavailable NMDA Antagonist With Improved Separation Between Antidepressant and Ataxic Doses Compared to Ketamine". Biological Psychiatry. 93 (9): S308–S309. doi:10.1016/j.biopsych.2023.02.771.
  8.  Hughes Z (December 2024). "ACNP 63rd Annual Meeting: Panels, Mini-Panels and Study Groups: 19.4 Translational Profile of GM-1020, a Novel Orally Bioavailable NMDA Receptor Antagonist That Achieves Robust Target Engagement Without Dissociation or Sedation". Neuropsychopharmacology. 49 (Suppl 1): 1–64 (25–25). doi:10.1038/s41386-024-02010-1. PMC 11627185. PMID 39643632.
  9.  Kiss L, Klein A, Austin E, Dvorak D, Gatti S, Papp M, et al. (December 2022). "ACNP 61st Annual Meeting: Poster Abstracts P1 - P270: P215. GM-1020: A Novel, Orally Bioavailable NMDA Receptor Antagonist With Rapid and Robust Antidepressant Effects and Reduced Ataxia in Rodents". Neuropsychopharmacology. 47 (Suppl 1): 63–219 (185–186). doi:10.1038/s41386-022-01484-1. PMC 9714397. PMID 36456693.
  10.  Dvorak D, Christian E, Hughes Z, Klein A, Austin E, Kiss L, et al. (2024). "ACNP 63rd Annual Meeting: Poster Abstracts P1-P304: P87. GM-1020 (NMDA Antagonist) Vs GM-2505 (5-HT2A Agonist) - Distinct Mechanisms, Same Outcome?". Neuropsychopharmacology. 49 (S1): 65–235. doi:10.1038/s41386-024-02011-0. ISSN 0893-133X. PMC 11627186. Retrieved 19 January 2026.
  11.  Trunnell ER, Baines J, Farghali S, Jackson T, Jayne K, Smith R, et al. (August 2024). "The need for guidance in antidepressant drug development: Revisiting the role of the forced swim test and tail suspension test". Regulatory Toxicology and Pharmacology. 151 105666. doi:10.1016/j.yrtph.2024.105666. PMID 38942190.
  12.  Sá VL, de Jesus Santos G, da Fonseca Fraga I, da Silva JM, Santos, MG, et al. (2015). Avaliação farmacológica de um análogo a um antagonista do receptor N-Metil-D-Aspartato [Pharmacological evaluation of an analogue of an N-Methyl-D-Aspartate receptor antagonist] (PDF). I Congresso de Ciências Farmacêuticas do Interior Baiano. [Translated:] [...] ketamine has low oral availability and a narrow therapeutic index, generating adverse effects such as dissociation, cognitive impairment, sedation, and ataxia, which limits the acceptance of the drug in the treatment of depression. The preclinical characterization through in vitro and in vivo studies of GM-1020 ((R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one) may indicate a new therapy that presents bioavailability when administered orally and absence of undesirable motor effects.
  13.  Gunther M (31 January 2023). "Gilgamesh Tweaks Known Psychedelics To Improve Therapies". Lucid News - Psychedelics, Consciousness Technology, and the Future of Wellness. Retrieved 20 February 2025.
Clinical data
Other namesGM-1020; GM1020; (R)-4-Fluorodeschloroketamine; (R)-4-FDCK; (R)-4FDCK
Routes of
administration		Oral[1][2][3]
Drug classNMDA receptor antagonist[1][2][3]
Pharmacokinetic data
Bioavailability>60%[4]
Elimination half-life4.3 hours[4]
Identifiers
IUPAC name
CAS Number2881017-49-6
PubChem CID156552274
Chemical and physical data
FormulaC13H16FNO
Molar mass221.275 g·mol−1
3D model (JSmol)Interactive image
SMILES
InChI

///////////blixeprodil, N-methyl-D-aspartate (NMDA) receptor antagonist, GM-1020, GM1020, (R)-4-Fluorodeschloroketamine, (R)-4-FDCK, (R)-4FDCK, S2MGG2PC5K

#blixeprodil, #N-methyl-D-aspartate (NMDA) receptor antagonist, #GM-1020, #GM1020, #(R)-4-Fluorodeschloroketamine, #(R)-4-FDCK, #(R)-4FDCK, #S2MGG2PC5K

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Bretisilocin

 

Bretisilocin

CAS2698331-35-8

MF C13H17FN2 MW220.29 g/mol

N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine
serotonin (5-HT2A) receptor agonist, GM-2505, GM 2505, 5-Fluoro-N-methyl-N-ethyltryptamine, 5F-MET, 5-F-MET, 5-Fluoro-MET, DS425RQ8SX

Bretisilocin, also known by its developmental code name GM-2505 and as 5-fluoro-N-methyl-N-ethyltryptamine (5F-MET or 5-fluoro-MET), is a serotonergic psychedelic of the tryptamine family which is under development for the treatment of major depressive disorder.[1][7][2][3] It is an analogue of dimethyltryptamine (DMT) and is the 5-fluorinated derivative of methylethyltryptamine (MET).[8] Bretisilocin's route of administration is intravenous infusion.[1][2][3][4]

The drug acts as a potent and well-balanced serotonin 5-HT2A and 5-HT2C receptor agonist, serotonin 5-HT2B receptor partial agonist or antagonist, and serotonin releasing agent.[2][9][8][10] It produces psychedelic-like effects in animals and similarly produces robust hallucinogenic effects in humans.[9][3] The duration of bretisilocin is 60 to 90 minutes and is intermediate between the durations of DMT and psilocybin.[6][11][4][12][8][2] It has been regarded by its developer as an "improved version of DMT".[12]

Bretisilocin was first described in the literature by 2022.[9][10] It is under development by Gilgamesh Pharmaceuticals.[1] As of June 2025, the drug is in phase 2 clinical trials for the treatment of major depressive disorder.[1] Bretisilocin was acquired from Gilgamesh Pharmaceuticals by AbbVie in a deal worth up to $1.2 billion in August 2025.[13][14] It was encountered as a novel recreational designer drug in 2026.[5]

Chemistry

Bretisilocin, also known as 5-fluoro-N-methyl-N-ethyltryptamine, is a substituted tryptamine derivative.[8] It is a derivative of dimethyltryptamine (DMT) and methylethyltryptamine (MET) as well as of 5-fluorotryptamine (5-FT).[6][8]

Synthesis

The chemical synthesis of bretisilocin has been described.[10]

Analogues

Some analogues of bretisilocin include 5-fluoro-DMT, 5-fluoro-DET, 5-fluoro-EPT, 5-chloro-DMT, 5-bromo-DMT, 5-fluoro-AMT, 5-fluoro-AET, 5-MeO-MET, and 7-F-5-MeO-MET, among others.

History

Bretisilocin was first described in the scientific literature by at least 2022.[9][10] It was patented by Jason Wallach and colleagues at the University of the Sciences in Philadelphia that year.[10] The drug was encountered as a novel recreational designer drug in March 2026.[5]

Society and culture

Names

Bretisilocin is the generic name of the drug and its INNTooltip International Nonproprietary Name.[16] It is also known by its developmental code name GM-2505.[1][9][3]

Legal status

Canada

Bretisilocin is not a controlled substance in Canada as of 2025.[17]

United States

Bretislocin is not an explicitly controlled substance in the United States.[18] However, it could be considered a controlled substance under the Federal Analogue Act if intended for human consumption.

Research

Bretisilocin is under development as a potential pharmaceutical drug by Gilgamesh Pharmaceuticals.[1] As of June 2025, it is in phase 2 clinical trials for the treatment of major depressive disorder.[1] A phase 2a trial of bretisilocin for major depressive disorder has been completed and the efficacy and safety data for the trial have been released.[1][19][20][21] The drug has since been acquired from Gilgamesh Pharmaceuticals by AbbVie in a deal worth up to $1.2 billion.[13][14] In 2026 bretisilocin entered European Medicines Agency’s priority medicines (PRIME) scheme for major depressive disorder.[22][23]

SYN

US20240286998,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US437765342&_cid=P12-MNXZVV-01144-1

Example 12: N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine (12)

Synthesis of N-[2-(5-fluoro-1H-indol-3-yl)ethyl]formamide

 To a solution of 5-fluorotryptamine hydrochloride (3 g, 14.0 mmol) in H 2O (200 mL) with stirring was added KOH until a precipitate was obtained. The aqueous mixture was extracted with EtOAc (3×70 mL), the organic phases were pooled, washed with brine, dried over anhydrous Na 2SO 4, and concentrated in vacuo. Residual EtOAc was removed by azeotropic distillation with ethyl formate (3×20 mL). The resulting 5-fluorotryptamine free base was transferred to a 30 mL oven-dried microwave vessel containing 3 Å molecular sieves (3.3 g). Ethyl formate (20 mL, 248 mmol) was added to the microwave vessel and the mixture was reacted for 2.5 h at 80° C. with 150 W in a microwave reactor. Upon completion, ethyl formate was removed under reduced pressure to provide N-[2-(5-fluoro-1H-indol-3-yl)ethyl]formamide (1.7 g, 8.24 mmol, 58.9% yield). The product was used in the subsequent reaction without further purification.

 To a solution of 5-fluorotryptamine hydrochloride (3 g, 14.0 mmol) in H 2O (200 mL) with stirring was added KOH until a precipitate was obtained. The aqueous mixture was extracted with EtOAc (3×70 mL), the organic phases were pooled, washed with brine, dried over anhydrous Na 2SO 4, and concentrated in vacuo. Residual EtOAc was removed by azeotropic distillation with ethyl formate (3×20 mL). The resulting 5-fluorotryptamine free base was transferred to a 30 mL oven-dried microwave vessel containing 3 Å molecular sieves (3.3 g). Ethyl formate (20 mL, 248 mmol) was added to the microwave vessel and the mixture was reacted for 2.5 h at 80° C. with 150 W in a microwave reactor. Upon completion, ethyl formate was removed under reduced pressure to provide N-[2-(5-fluoro-1H-indol-3-yl)ethyl]formamide (1.7 g, 8.24 mmol, 58.9% yield). The product was used in the subsequent reaction without further purification.

Synthesis of 2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine

  A three neck 500 mL round bottom flask, 300 mL addition funnel, stir bar, and condenser were dried overnight in an oven at 70° C., then further dried with external heat while flushing argon through the sealed system. Once drying was deemed completion the round bottom flask was placed into an ice bath (0° C.), and the apparatus was allowed to cool to room temperature. THF (100 mL) was added via the addition funnel and was allowed to reach 0° C., then sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al) (18.41 mL, 59.6 mmol) was added to the reaction vessel. Next, N-[2-(5-fluoro-1H-indol-3-yl)ethyl]formamide (4.1 g, 19.8 mmol) in THE (20 mL) was added dropwise to the reaction vessel, with stirring, under argon over 30 mins at 0° C. Following the addition, the reaction was heated at reflux for 4 h. Upon completion, the reaction was cooled to 0° C. and cautiously quenched by the dropwise addition of THF/H 2O (1:1, v/v) with ice. Once quenched a small amount of KOH (aq.), then 100 mL of EtOAc were added.
      The inorganic solids were then gravity filtered and washed with EtOAc. The filtrate was extracted with 0.2 M HCl (aq.) (3×166 mL). The pooled aqueous phases were then basified with KOH pellets and extracted with EtOAc (3×100 mL). The pooled organic extractions were washed with brine (20 mL), dried over anhydrous Na 2SO 4, and concentrated in vacuo to provide 2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine as a yellow oil (3.14 g, 0.0163 mol, 82.32% yield). The product was used in the subsequent reaction without further purification. ASAP-MS: m/z 193.2 (theoretical [M+H] +, C 11H 13FN 2 +), m/z 193.2 (observed).

Synthesis of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine (12)

N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine (12) was synthesized in a similar manner as described above for N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-propylpropan-1-amine (5), starting from 2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine (0.7 g, 3.64 mmol), and acetaldehyde (0.96 g, 21.8 mmol), to provide the title compound as a colorless oil after purification by column chromatography using silica gel as a stationary phase and 20% EtOH/EtOAc (1% Et 3N v/v) as the mobile phase (0.62 g, 2.81 mmol, 77.2% yield), and subsequently the corresponding HCl salt as a white crystalline solid. HR-ASAP-MS: m/z 221.1442 (theoretical [M+H] +, C 13H 18FN 2 +), m/z 221.1449 (observed, Δ=−3.2 ppm). 1H-NMR (400 MHz, d 6-DMSO) δ 11.15 (s, 1H), 10.74 (s, 1H), 7.44 (dd, J=10.1, 2.5 Hz, 1H), 7.36 (dd, J=8.8, 4.6 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 6.93 (dt, J=9.2, 2.5 Hz, 1H), 3.31-3.13 (m, 4H), 3.13-3.05 (m, 2H), 2.78 (d, J=3.1 Hz, 3H), 1.26 (t, J=7.3 Hz, 3H). 13C-NMR (101 MHz, d 6-DMSO) δ 156.74 (d, J=231.1 Hz, 1C), 132.88 (s, 1C), 126.96 (d, J=10.0 Hz, 1C), 125.42 (s, 1C), 112.48 (d, J=9.9 Hz, 1C), 109.51 (s, 1C), 109.32 (d, J=26.0 Hz, 1C), 103.13 (d, J=23.1 Hz, 1C), 54.37 (s, 1C), 49.82 (s, 1C), 38.13 (s, 1C), 19.68 (s, 1C), 8.79 (s, 1C). 19F-NMR (377 MHz, d 6-DMSO) δ−124.79 (s, 1F).

PAT

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PAT

Methods of treating mood disorders

Publication Number: US-2022041551-A1

Priority Date: 2020-02-18

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References

References

  1.  "GM 2505". AdisInsight. 5 June 2025. Retrieved 29 July 2025.
  2.  Marek GJ, Makai-Bölöni S, Umbricht D, Christian EP, Winters J, Dvorak D, et al. (2025). "A novel psychedelic 5-HT 2A receptor agonist GM-2505: The pharmacokinetic, safety, and pharmacodynamic profile from a randomized trial healthy volunteer". Journal of Psychopharmacology 02698811251378512. doi:10.1177/02698811251378512. hdl:1887/4298848. PMID 41099491.
  3.  Hughes Z, Christian E, Dvorak D, Umbricht D, Winters J, Raines S, et al. (December 2023). "ACNP 62nd Annual Meeting: Poster Abstracts P1 - P250: P238. Subjective and Pharmacodynamic Effects of the Novel 5-HT2A Receptor Agonist GM-2505 in Healthy Volunteers Show High Translatability From Rodent Data and Hold Promise for Future Development in Patients With Depression". Neuropsychopharmacology. 48 (Suppl 1). Springer Science and Business Media LLC: 63–210 (202–203). doi:10.1038/s41386-023-01755-5. PMC 10729595. PMID 38040809.
  4.  Umbricht D, Christian E, Winters J, Raines S, Hughes ZA, Leong W, et al. (2024). "Pharmacokinetic, pharmacodynamic and subjective and effects of the novel 5-HT2A receptor agonist GM-2505 in healthy volunteers". Neuroscience Applied. 3 104845. doi:10.1016/j.nsa.2024.104845.
  5.  "Бретисилоцин (5F-MET)". АИПСИН (in Russian). Retrieved 18 March 2026.
  6.  Peplow M (22 June 2024). "Should Next-Generation Psychedelics Skip the Trip?". Scientific American. Retrieved 20 February 2025. Gilgamesh is also working on GM-2505, a 5-HT2A agonist that is structurally related to psilocybin and DMT. GM-2505 completed a phase 1 trial late last year and should enter phase 2 for major depressive disorder this year. Its psychedelic effect lasts 60 to 90 minutes — long enough for patients to "explore the altered state of consciousness that might be needed for long-term durable efficacy," Krugel says, yet within a timeframe that is manageable for healthcare systems. "Personally, I believe that the hallucinogenic effects are an important component, as multiple hallucinogenic compounds have demonstrated durable, transformational changes from a single dose in human studies," he adds.
  7.  Witkin JM, Golani LK, Smith JL (April 2023). "Clinical pharmacological innovation in the treatment of depression". Expert Review of Clinical Pharmacology. 16 (4): 349–362. doi:10.1080/17512433.2023.2198703. PMID 37000975. GM-2505 is a dual-acting compound with both agonist activity at 5-HT 2A receptors and a releaser of 5-HT. [...]
  8.  "Methods of treating mood disorders". Google Patents. 2022. Retrieved 14 November 2024.
  9.  Hughes Z, Klein A, Austin E, Dvorak D, Gatti S, Kiss L, et al. (December 2022). "ACNP 61st Annual Meeting: Poster Abstracts P1 - P270: P254. Gm-2505 is a Novel 5-Ht2a Receptor Agonist and 5-Ht Releaser That Induces Rapid, Robust, and Durable Antidepressant Effects at Doses Associated With Decreased Power in Low Frequency EEG Bands in Rats". Neuropsychopharmacology. 47 (Suppl 1): 63–219 (209–209). doi:10.1038/s41386-022-01484-1. PMC 9714397. PMID 36456693.
  10.  WO 2022/256554, Wallach J, Dybek M, "Fluorinated Tryptamine Compounds, Analogues Thereof, and Methods Using Same", published 8 December 2022, assigned to University of the Sciences in Philadelphia[...] Synthesis of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine (12) [structure] N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine (12) was synthesized [...] [...] Table 1. Selected compounds of the present invention. [...] [Compound 12:] [...] Table 3. Functional Activity of Compounds at 5-HT2A (Ca2+), 5-HT2B (Ca2+), 5-HT2c (Ca2+), and 5-HT1A (cAMP inhibition) [...]
  11.  Hughes Z, Klein A, Dvorak D, Austin E, Kiss L, Marek G, et al. (2023). "22. GM-2505 has Rapid Onset Antidepressant Activity and Causes Dose-Dependent Changes in qEEG With Increasing 5-HT2A Receptor Occupancy". Biological Psychiatry. 93 (9): S102–S103. doi:10.1016/j.biopsych.2023.02.262.
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  16.  https://iris.who.int/bitstream/handle/10665/380497/9789240107038-eng.pdf "bretisilocinum bretisilocin N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine serotonin (5-HT2A) receptor agonist"
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External links

Clinical data
Other namesGM-2505; GM2505; 5-Fluoro-N-methyl-N-ethyltryptamine; 5F-MET; 5-F-MET; 5-Fluoro-MET
Routes of
administration		Intravenous,[1][2][3][4] intranasal[5]
Drug classSerotonergic psychedelic; Hallucinogen; Serotonin 5-HT2A and 5-HT2C receptor agonist; Serotonin 5-HT2B receptor partial agonist or antagonist; Serotonin releasing agent
Legal status
Legal statusInvestigational
Pharmacokinetic data
Onset of actionIVTooltip Intravenous injection: 10–20 minutes (peak)[2]
Elimination half-life45 (40–50) minutes[2][3]
Duration of actionIVTooltip Intravenous injection: 60–90 minutes[2][6]
Identifiers
IUPAC name
CAS Number2698331-35-8 
PubChem CID156836209
ChemSpider129221851
ChEMBLChEMBL5028766
Chemical and physical data
FormulaC13H17FN2
Molar mass220.291 g·mol−1
3D model (JSmol)Interactive image
SMILES
InChI

//////////bretisilocin, serotonin (5-HT2A) receptor agonist, GM-2505, GM 2505, 5-Fluoro-N-methyl-N-ethyltryptamine, 5F-MET, 5-F-MET, 5-Fluoro-MET, DS425RQ8SX

#bretisilocin, #serotonin (5-HT2A) receptor agonist, #GM-2505, #GM 2505, #5-Fluoro-N-methyl-N-ethyltryptamine, #5F-MET, #5-F-MET, #5-Fluoro-MET, #DS425RQ8SX

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