Chemistry:ITI-1549

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ITI-1549 is a putatively non-hallucinogenic serotonin 5-HT2A receptor agonist which is under development for the treatment of mood disorders and other psychiatric disorders.[1][2][3][4][5] In addition to acting at the serotonin 5-HT2A receptor, it is also an antagonist of the serotonin 5-HT2B receptor and an agonist of the serotonin 5-HT2C receptor.[5][6] The drug's route of administration has not been specified.[1]

Pharmacology

Pharmacodynamics

Serotonergic psychedelics like psilocybin and lysergic acid diethylamide (LSD) are agonists of the serotonin 5-HT2A receptor that activate both the β-arrestin and Gq signaling pathways.[5] In 2023, activation of the Gq pathway, but not the β-arrestin pathway, was linked with the production of hallucinogenic-like effects, specifically the head-twitch response (HTR), in animals.[5][7][8][9] Serotonin 5-HT2A receptor agonists are of interest for the potential treatment of psychiatric disorders like depression and anxiety, but the hallucinogenic effects of serotonergic psychedelics serve as a barrier and partial limiting factor in this regard.[10][11]

ITI-1549 has high affinity for the serotonin 5-HT2A receptor (Ki = 10.2 nM) and acts as a partial agonist of the β-arrestin pathway with an intrinsic activity of 72% (relative to α-methylserotonin).[5] Conversely, unlike serotonergic psychedelics, ITI-1549 does not activate the Gq pathway.[5] Hence, it is a biased agonist of the serotonin 5-HT2A receptor.[5] In accordance with the preceding, ITI-1549 does not produce the HTR, a behavioral proxy of psychedelic effects, in animals.[5][12][13] However, similarly to serotonergic psychedelics, ITI-1549 has been found to produce anxiolytic-like and prosocial effects in animals.[5] Antidepressant-like and psychoplastogenic effects of ITI-1549 in animals have yet to be assessed or reported.[5] In any case, various other non-hallucinogenic serotonin 5-HT2A receptor agonists selective for the β-arrestin pathway have been found to produce antidepressant-like effects in animals.[8][10][14]

In addition to the serotonin 5-HT2A receptor, ITI-1549 has high affinity for the serotonin 5-HT2B receptor (Ki = 4.8 nM).[5] However, it acts as an antagonist of this receptor rather than as an agonist (IC50 = 13.8 nM).[5] Based on these findings, continuous administration of ITI-1549 is not expected to pose a risk of cardiac valvulopathy.[5] This is in contrast to many serotonergic psychedelics, which have been shown to act as potent serotonin 5-HT2B receptor agonists.[15][16] ITI-1549 is additionally a potent agonist of the serotonin 5-HT2C receptor (Ki = 21 nM; EC50 = 40 nM).[6]

Chemistry

The drug is a small molecule, but its chemical structure does not yet seem to have been disclosed.[1][2] It is said to be chemically unrelated to existing plant-derived and synthetic serotonergic psychedelics.[5] However, its structure was disclosed in a 2024 patent.[6] It is structurally related to the atypical antipsychotic lumateperone.[6]

Clinical trials

As of February 2024, ITI-1549 is in the preclinical stage of development for psychiatric disorders.[1][2][4] A phase 1 clinical trial is being planned and is expected to commence in late 2024 or early 2025.[17] The drug is under development by Intra-Cellular Therapies.[1][2][4] ITI-1549 was first described in the scientific literature by 2023.[5]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "ITI 1549". 15 January 2024. https://adisinsight.springer.com/drugs/800076459. 
  2. ↑ 2.0 2.1 2.2 2.3 "Delving into the Latest Updates on ITI-1549 with Synapse". 12 October 2024. https://synapse.patsnap.com/drug/567cc77a5bfc4da390530a0aa1bc0c9a. 
  3. ↑ "Pipeline". https://www.intracellulartherapies.com/pipeline/. "Pipeline: [...] ITI-1500 Series: ITI-1549 – Mood and Other Neuropsychiatric Disorders [...] ITI-1500 series is our portfolio of Non-Hallucinogenic Psychedelics. ITI-1549 is our lead product candidate in this program." 
  4. ↑ 4.0 4.1 4.2 Intra-Cellular Therapies (22 February 2024). "Intra-Cellular Therapies Reports Fourth Quarter And Full-Year 2023 Financial Results And Provides Corporate Update". https://www.globenewswire.com/news-release/2024/02/22/2833584/0/en/Intra-Cellular-Therapies-Reports-Fourth-Quarter-And-Full-Year-2023-Financial-Results-And-Provides-Corporate-Update.html. "ITI-1500 Non-Hallucinogenic Psychedelic Program: In 2023, we introduced the ITI-1500 program. This program is focused on the development of novel non-hallucinogenic psychedelics for the treatment of mood, anxiety and other neuropsychiatric disorders without the liabilities of known psychedelics, including the hallucinogenic potential and risk for cardiac valvular pathologies. Our lead product candidate in this program, ITI-1549, is advancing through IND enabling studies and is expected to enter human testing in late 2024 or early 2025." 
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 "ACNP 62nd Annual Meeting: Poster Abstracts P251 - P500: P358. Discovery and Characterization of ITI-1549, a Novel Non-Hallucinogenic Psychedelic for the Treatment of Neuropsychiatric Disorders". Neuropsychopharmacology 48 (Suppl 1): 211–354 (272–273). December 2023. doi:10.1038/s41386-023-01756-4. PMID 38040810. 
  6. ↑ 6.0 6.1 6.2 6.3 Li P, Davis R, Snyder G, Zhang L, Zheng G , Quai Y, Zhang Q, "Heterocycle fused gamma-carbolines acting on the serotonine 5-ht2a receptor", WO patent 2024145659, published 4 July 2024 Quote: Examples 1 to 180 are, or will be, synthesized and characterized: [...] Ex.: 40. X: -N(CH3)-. Y: Cyp. m: 1. n: 2. Z: bond. A: benzo[d]isoxazol-3-yl [...] Examples 24, 25, and 40, also show zero G-q mediated agonist activity, but while the compound of Example 24 is a beta-arrestin antagonist, the compounds of Examples 25 and 40 are beta-arrestin partial agonists. [...] The following receptor affinity results are obtained (with the Compound of Formula A for comparison): [...] Ex.: 40. 5-HT2A (%): 87%. 5-HT2A Ki: 10. [...] Selected compounds are also tested in receptor binding assays for the 5-HT2B, and/or 5-HT2C receptors. Some results are shown in the following table: Ex.: 40. 5-HT2A (%): 87%. 5-HT2A Ki: 10. 5-HT2B (%): 80%. 5-HT2B Ki: 4.8. 5-HT2C (%): 81%. 5-HT2C Ki: 21.
  7. ↑ "1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents - A Review". ACS Pharmacology & Translational Science 7 (6): 1722–1745. June 2024. doi:10.1021/acsptsci.4c00157. PMID 38898956. "Although the specific signaling cascades mediating the HTR have not been conclusively identified, Gq and β-arrestin2 have been implicated. Recent studies with different existing and novel agents, including DOI, found that the HTR was correlated with Gq efficacy but not with β-arrestin2 recruitment.114". 
  8. ↑ 8.0 8.1 "Neurobiology of the Antidepressant Effects of Serotonergic Psychedelics: A Narrative Review". Current Treatment Options in Psychiatry (Springer Science and Business Media LLC) 11 (2): 90–105. 26 April 2024. doi:10.1007/s40501-024-00319-8. ISSN 2196-3061. 
  9. ↑ "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential". Nat Commun 14 (1): 8221. December 2023. doi:10.1038/s41467-023-44016-1. PMID 38102107. 
  10. ↑ 10.0 10.1 "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants". Chemical Reviews 124 (1): 124–163. January 2024. doi:10.1021/acs.chemrev.3c00375. PMID 38033123. 
  11. ↑ "Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties". Psychopharmacology. May 2024. doi:10.1007/s00213-024-06599-5. PMID 38743110. 
  12. ↑ "Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model". Drug Testing and Analysis 4 (7-8): 556–576. 2012. doi:10.1002/dta.1333. PMID 22517680. 
  13. ↑ "Animal Models and Hallucinogenic Drugs". The Neuroscience of Hallucinations. New York, NY: Springer New York. 2013. p. 253–277. doi:10.1007/978-1-4614-4121-2_14. ISBN 978-1-4614-4120-5. 
  14. ↑ "Structure-based discovery of nonhallucinogenic psychedelic analogs". Science 375 (6579): 403–411. January 2022. doi:10.1126/science.abl8615. PMID 35084960. 
  15. ↑ "The risk of chronic psychedelic and MDMA microdosing for valvular heart disease". Journal of Psychopharmacology 37 (9): 876–890. September 2023. doi:10.1177/02698811231190865. PMID 37572027. 
  16. ↑ "Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: Comparison to known cardiotoxins". Journal of Psychopharmacology 38 (3): 217–224. March 2024. doi:10.1177/02698811231225609. PMID 38214279. 
  17. ↑ "A study of ITI-1549". 28 February 2024. https://adisinsight.springer.com/trials/700371344. 



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