Zalsupindole

Zalsupindole
Above: structure of zalsupindole Below: 3D representation of a zalsupindole molecule
Clinical data
Other namesZAL; DLX-001; DLX-1; DLX001; DLX1; AAZ-A-154; AAZ; (R)-5-Methoxy-N,N-dimethyl-α-methylisotryptamine; (R)-5-MeO-α-methyl-isoDMT; (R)-5-MeO-N,N-dimethyl-isoAMT
Routes of
administration		Oral[1][2][3]
Drug classNon-hallucinogenic serotonin 5-HT2A receptor agonist; Psychoplastogen
ATC code
  • None
Identifiers
IUPAC name
  • (2R)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine
CAS Number
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC14H20N2O
Molar mass232.327 g·mol−1
3D model (JSmol)
SMILES
  • CN(C)[C@H](C)Cn1ccc2cc(ccc21)OC
InChI
  • InChI=1S/C14H20N2O/c1-11(15(2)3)10-16-8-7-12-9-13(17-4)5-6-14(12)16/h5-9,11H,10H2,1-4H3/t11-/m1/s1
  • Key:KHEUWLQKCXGVEL-LLVKDONJSA-N

Zalsupindole, also known by its code names DLX-001 and AAZ-A-154 and as (R)-5-methoxy-N,N-dimethyl-α-methylisotryptamine ((R)-5-MeO-α-Me-isoDMT), is non-hallucinogenic serotonin receptor agonist and psychoplastogen of the isotryptamine family related to psychedelic tryptamines such as dimethyltryptamine (DMT).[1][2][4][5][6] It is under development for the treatment of major depressive disorder and other central nervous system disorders.[2][4] The drug is taken orally.[1][2][3]

It acts as a partial agonist of the serotonin 5-HT2A receptor and also interacts with other serotonin receptors.[1] The drug activates the serotonin 5-HT2A receptor with sufficiently high efficacy to promote neuroplasticity but not with adequate efficacy to cause psychedelic effects.[1] It does not produce psychedelic-like effects in animals or humans but does produce antidepressant-like effects in animals.[1][3]

Zalsupindole was first described in the scientific literature by 2021.[7] It was developed by David E. Olson and colleagues at the University of California, Davis and Delix Therapeutics.[2][4] As of December 2024, it is in phase 1 clinical trials and a phase 2 trial is being planned.[2]

Use and effects

A phase 1 dose-ranging clinical trial found that zalsupindole is non-hallucinogenic in humans across a dose range of 2 to 360 mg orally.[1][3] Nonetheless, it produced changes in brain function as measured by quantitative electroencephalography (qEEG).[3]

Side effects

Side effects of zalsupindole include dose-dependent nausea, headache, and dizziness.[3]

Pharmacology

Pharmacodynamics

Zalsupindole is a non-selective serotonin receptor modulator including of the serotonin 5-HT2A receptor.[1][8] It acts as a low-potency, low-efficacy partial agonist of the serotonin 5-HT2A receptor, with an EC50Tooltip half-maximal effective concentration of 8,200 nM and an EmaxTooltip maximal efficacy of 17%.[1] The drug is also a moderate-efficacy partial agonist of the serotonin 5-HT2C receptor, with an EC50 of 3,300 nM and an Emax of 70%.[1] Other activities have also been reported.[1] It is selective for the serotonin 5-HT2 receptors over a number of other receptors, including dopamine receptors, adrenergic receptors, and the κ-opioid receptor, among others.[1][8] The drug is a silent antagonist of the serotonin 5-HT2B receptor, with an IC50Tooltip half-maximal inhibitory concentration of 27,600 nM.[1][6]

Zalsupindole is orally bioavailable and centrally penetrant in animals.[6] It is a psychoplastogen via activation of the serotonin 5-HT2A receptor and rapidly and persistently increases neuroplasticity in preclinical research.[1][9][5][6] Animal studies have found that it produces antidepressant-like effects without causing psychedelic-like effects such as the head-twitch response.[1][7][10][5][6][11] It does not produce hyperlocomotion at therapeutically relevant doses.[1] In accordance with its serotonin 5-HT2B receptor antagonism, zalsupindole showed no cardiovascular safety signals in animals.[6]

Pharmacokinetics

The pharmacokinetics of zalsupindole have been studied.[1][3]

Chemistry

Zalsupindole, also known as (R)-5-methoxy-N,N-dimethyl-α-methylisotryptamine, is a substituted isotryptamine derivative.[12][13] It is a combined derivative of 5-methoxy-N,N-dimethylisotryptamine (5-MeO-isoDMT) and α-methylisotryptamine (isoAMT).[12][13] Another related compound is 6-methoxy-N,N-dimethylisotryptamine (6-MeO-isoDMT).[12] Zalsupindole is a close isotryptamine analogue of α,N,N,O-tetramethylserotonin (α,N,N,O-TMS or 5-MeO-α,N,N-TMT).[13]

History

Zalsupindole was first described in the scientific literature by David E. Olson and colleagues in 2021.[7] It was developed by Olson's lab at the University of California, Davis and at his company Delix Therapeutics.[2][4] The drug was initially described under the name AAZ-A-154 and then by the name DLX-001 before receiving the name zalsupindole.[2][4][1]

Society and culture

Names

Zalsupindole is the generic name of the drug and its INNTooltip International Nonproprietary Name.[14] It is also known by its developmental code names DLX-001 and AAZ-A-154.[2][4]

Research

Zalsupindole, as well as related drugs such as tabernanthalog (TBG; DLX-007), DLX-159, DLX-2270, and JRT, are licensed by Delix Therapeutics and are being developed for treatment of neuropsychiatric disorders such as depression and schizophrenia.[9][2][4] As of December 2024, zalsupindole is in phase 1 clinical trials for major depressive disorder and other central nervous system disorders.[2][4] A phase 2 trial is being planned.[2]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Agrawal R, Gillie D, Mungenast A, Chytil M, Engel S, Wu MC, et al. (October 2025). "Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics". ACS Chem Neurosci acschemneuro.5c00667. doi:10.1021/acschemneuro.5c00667. PMID 41078264.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 "DLX 1". AdisInsight. 11 December 2023. Retrieved 2 November 2024.
  3. 1 2 3 4 5 6 7 Koenig A, van der Aa L, Pelletier N, Patat A, Viardot G, Olson D, et al. (2024). "ACNP 63rd Annual Meeting: Poster Abstracts P1-P304: P163. Phase I Results for DLX-001, a Novel Neuroplastogen Under Development for the Treatment of Major Depressive Disorder" (PDF). Neuropsychopharmacology. 49 (S1): 65–235 (157–158). doi:10.1038/s41386-024-02011-0. ISSN 0893-133X. PMC 11627186. PMID 39643633. Retrieved 31 January 2025.
  4. 1 2 3 4 5 6 7 8 "Delving into the Latest Updates on DLX-001 with Synapse". Synapse. 1 November 2024. Retrieved 2 November 2024.
  5. 1 2 3 Rasmussen K, Chytil M, Agrawal R, Leach P, Gillie D, Mungenast A, et al. (2024). "14. Preclinical Pharmacology of DLX-001, a Novel Non-Hallucinogenic Neuroplastogen With the Potential for Treating Neuropsychiatric Diseases". Biological Psychiatry. 95 (10). Elsevier BV: S80. doi:10.1016/j.biopsych.2024.02.192. ISSN 0006-3223.
  6. 1 2 3 4 5 6 Rasmussen K, Engel S, Chytil M, Koenig A, Meyer R, Rus M, et al. (December 2023). "ACNP 62nd Annual Meeting: Poster Abstracts P251 - P500: P361. Preclinical Pharmacology of DLX-001, a Novel Non-Hallucinogenic Neuroplastogen With the Potential for Treating Neuropsychiatric Diseases". Neuropsychopharmacology. 48 (Suppl 1): 211–354 (274–275). doi:10.1038/s41386-023-01756-4. PMC 10729596. PMID 38040810.
  7. 1 2 3 Dong C, Ly C, Dunlap LE, Vargas MV, Sun J, Hwang IW, et al. (May 2021). "Psychedelic-inspired drug discovery using an engineered biosensor". Cell. 184 (10): 2779–2792.e18. doi:10.1016/j.cell.2021.03.043. PMC 8122087. PMID 33915107.
  8. 1 2 Dunlap LE (2022). Development of Non-Hallucinogenic Psychoplastogens (Thesis). University of California, Davis. Retrieved 18 November 2024.
  9. 1 2 "Can we take the high out of psychedelics?". Wired UK. ISSN 1357-0978. Retrieved 2022-07-07.
  10. ↑ WO 2020176597, Olson DE, Dunlap L, Wagner FF, "N-substituted indoles and other heterocycles for treating brain disorders", published 3 September 2020, assigned to The Regents of the University of California
  11. ↑ Cross R (2021-09-27). "Delix raises $70 million to synthesize psychedelic-inspired drugs". cen.acs.org. Archived from the original on 2021-09-27. Retrieved 2022-01-14.
  12. 1 2 3 Duan W, Cao D, Wang S, Cheng J (January 2024). "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants". Chem Rev. 124 (1): 124–163. doi:10.1021/acs.chemrev.3c00375. PMID 38033123.
  13. 1 2 3 "(2R)-1-(5-Methoxyindol-1-yl)-N,N-dimethylpropan-2-amine". PubChem. Retrieved 27 November 2024.
  14. ↑ https://iris.who.int/bitstream/handle/10665/380497/9789240107038-eng.pdf "zalsupindolum zalsupindole (2R)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine antidepressant"
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