Chemistry:Zalsupindole

From HandWiki

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][3][4][5][6] It is under development for the treatment of major depressive disorder and other central nervous system disorders.[3][4] The drug is taken orally.[1][2][3][7]

It acts as a partial agonist of the serotonin 5-HT2A receptor and also interacts with other serotonin receptors.[1][2] 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][2] It does not produce psychedelic-like effects in animals or humans but does produce antidepressant-like effects in animals.[1][2][7]

Zalsupindole was first described in the scientific literature by 2021.[1][8] It was developed by David E. Olson and colleagues at the University of California, Davis and Delix Therapeutics.[1][3][4] As of January 2026, it is in phase 1 clinical trials and a phase 2 trial is being planned.[3][1][9]

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][2][7][9] Nonetheless, it produced changes in brain function as measured by quantitative electroencephalography (qEEG).[1][7][9]

Side effects

Side effects of zalsupindole include dose-dependent nausea, headache, and dizziness.[7][9]

Pharmacology

Pharmacodynamics

Zalsupindole is a non-selective serotonin receptor modulator including of the serotonin 5-HT2A receptor.[1][2][10] It acts as a low-potency, low-efficacy partial agonist of the serotonin 5-HT2A receptor, with an EC50 of 8,200 nM and an Emax of 17%.[1][2] 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][2] Other activities have also been reported.[1][2] It is selective for the serotonin 5-HT2 receptors over a number of other receptors, including the serotonin 5-HT1A receptor, dopamine receptors, adrenergic receptors, and the κ-opioid receptor, among others.[1][2][10] The drug is a silent antagonist of the serotonin 5-HT2B receptor, with an IC50 of 27,600 nM.[1][2][6]

Zalsupindole is orally bioavailable and centrally penetrant in animals.[1][6] It is a psychoplastogen via activation of the serotonin 5-HT2A receptor and rapidly and persistently increases neuroplasticity in preclinical research.[1][2][11][5][6] The serotonin 5-HT2A receptor antagonist ketanserin abolishes the psychoplastogenic effects of zalsupindole.[1] Zalsupindole produces comparable psychoplastogenic effects to serotonergic psychedelics like psilocin and dimethyltryptamine (DMT) as well as to the dissociative ketamine.[1] Animal studies have found that the drug produces antidepressant-like effects without causing psychedelic-like effects such as the head-twitch response.[1][2][8][12][5][6][13] It does not produce hyperlocomotion at therapeutically relevant doses.[2] In accordance with its serotonin 5-HT2B receptor antagonism, zalsupindole showed no cardiovascular safety signals in animals.[1][6]

Pharmacokinetics

The pharmacokinetics of zalsupindole have been studied.[1][2][7]

Chemistry

Zalsupindole, also known as (R)-5-methoxy-N,N-dimethyl-α-methylisotryptamine, is a substituted isotryptamine derivative.[1][14][15] It is a combined derivative of 5-methoxy-N,N-dimethylisotryptamine (5-MeO-isoDMT) and α-methylisotryptamine (isoAMT).[14][15] Another related compound is 6-methoxy-N,N-dimethylisotryptamine (6-MeO-isoDMT).[14] Zalsupindole is a close isotryptamine analogue of α,N,N,O-tetramethylserotonin (α,N,N,O-TMS or 5-MeO-α,N,N-TMT).[15]

Synthesis

The chemical synthesis of zalsupindole has been described.[1][12]

History

Zalsupindole was first described in the scientific literature by David E. Olson and colleagues in 2021.[1][8] It was developed by Olson's lab at the University of California, Davis and at his company Delix Therapeutics.[1][3][4] The drug wasfirst synthesized in 2019.[1] It was initially described under the name AAZ-A-154 and then by the name DLX-001 before receiving the name zalsupindole.[1][3][4][2]

Society and culture

Names

Zalsupindole is the generic name of the drug and its INN.[1][16] It is also known by its developmental code names DLX-001 and AAZ-A-154.[1][3][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.[1][11][3][4] As of January 2026, zalsupindole is in phase 1 clinical trials for major depressive disorder and other central nervous system disorders.[3][4] Phase 1a and 1b trials have been completed and results reported.[1][3][4][9] A phase 2 trial is being planned.[3][1][9]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 1.32 1.33 "Zalsupindole: A Non-Hallucinogenic Psychoplastogen Advancing Psychedelic-Inspired Therapeutics". ACS Chem Neurosci. January 2026. doi:10.1021/acschemneuro.5c00707. PMID 41493772. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 "Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics". ACS Chem Neurosci. October 2025. doi:10.1021/acschemneuro.5c00667. PMID 41078264. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 "DLX 1". 11 December 2023. https://adisinsight.springer.com/drugs/800063576. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 "Delving into the Latest Updates on DLX-001 with Synapse". 1 November 2024. https://synapse.patsnap.com/drug/853f1446b79348adad375cc77a9efb7e. 
  5. ↑ 5.0 5.1 5.2 "14. Preclinical Pharmacology of DLX-001, a Novel Non-Hallucinogenic Neuroplastogen With the Potential for Treating Neuropsychiatric Diseases". Biological Psychiatry (Elsevier BV) 95 (10): S80. 2024. doi:10.1016/j.biopsych.2024.02.192. ISSN 0006-3223. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "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). December 2023. doi:10.1038/s41386-023-01756-4. PMID 38040810. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 "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". Neuropsychopharmacology 49 (S1): 65–235 (157–158). 2024. doi:10.1038/s41386-024-02011-0. ISSN 0893-133X. PMID 39643633. PMC 11627186. https://www.nature.com/articles/s41386-024-02011-0.pdf. Retrieved 31 January 2025. 
  8. ↑ 8.0 8.1 8.2 "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. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 "ACNP 64th Annual Meeting: Poster Abstracts P1-P291: P231. A Phase Ib study to evaluate the pharmacodynamics, safety, and tolerability of the novel neuroplastogen Zalsupindole (DLX-001), dosed daily and intermittently in participants with major depressive Disorder". Neuropsychopharmacology 51 (S1): 74–242. 2026. doi:10.1038/s41386-025-02279-w. ISSN 0893-133X. https://www.nature.com/articles/s41386-025-02279-w. Retrieved 9 January 2026. 
  10. ↑ 10.0 10.1 Dunlap, Lee E. (2022). Development of Non-Hallucinogenic Psychoplastogens (Thesis). University of California, Davis. Retrieved 18 November 2024.
  11. ↑ 11.0 11.1 "Can we take the high out of psychedelics?" (in en-GB). Wired UK. ISSN 1357-0978. https://www.wired.co.uk/article/psychedelics-without-the-high. Retrieved 2022-07-07. 
  12. ↑ 12.0 12.1 Olson DE, Dunlap L, Wagner FF, "N-substituted indoles and other heterocycles for treating brain disorders", WO patent 2020176597, published 3 September 2020, assigned to The Regents of the University of California
  13. ↑ Cross, Ryan (2021-09-27). "Delix raises $70 million to synthesize psychedelic-inspired drugs". https://cen.acs.org/pharmaceuticals/neuroscience/Delix-raises-70-million-synthesize/99/web/2021/09. 
  14. ↑ 14.0 14.1 14.2 "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants". Chem Rev 124 (1): 124–163. January 2024. doi:10.1021/acs.chemrev.3c00375. PMID 38033123. 
  15. ↑ 15.0 15.1 15.2 "(2R)-1-(5-Methoxyindol-1-yl)-N,N-dimethylpropan-2-amine". https://pubchem.ncbi.nlm.nih.gov/compound/154694212. 
  16. ↑ 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"



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Zalsupindole&oldid=4245079"