ITI-1549

Serotonergic psychedelics like psilocybin and lysergic acid diethylamide (LSD) are agonists of the serotonin 5-HT_2A receptor that activate both the β-arrestin and G_q signaling pathways. In 2023, activation of the G_q pathway, but not the β-arrestin pathway, was linked with the production of hallucinogenic-like effects, specifically the head-twitch response (HTR), in animals.{{cite journal | vauthors = Glennon RA, Dukat M | title = 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 | journal = ACS Pharmacology & Translational Science | volume = 7 | issue = 6 | pages = 1722–1745 | date = June 2024 | pmid = 38898956 | doi = 10.1021/acsptsci.4c00157 | quote = 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 | doi-access = free | pmc = 11184610 }}{{cite journal | vauthors = Chisamore N, Kaczmarek E, Le GH, Wong S, Orsini DK, Mansur R, McIntyre RS, Rosenblat JD | title=Neurobiology of the Antidepressant Effects of Serotonergic Psychedelics: A Narrative Review | journal=Current Treatment Options in Psychiatry | publisher=Springer Science and Business Media LLC | volume=11 | issue=2 | date=26 April 2024 | issn=2196-3061 | doi=10.1007/s40501-024-00319-8 | pages=90–105}}{{cite journal | vauthors = Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, Hennessey JJ, Bock HA, Anderson EI, Sherwood AM, Morris H, de Klein R, Klein AK, Cuccurazzu B, Gamrat J, Fannana T, Zauhar R, Halberstadt AL, McCorvy JD | title = Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential | journal = Nat Commun | volume = 14 | issue = 1 | pages = 8221 | date = December 2023 | pmid = 38102107 | pmc = 10724237 | doi = 10.1038/s41467-023-44016-1 | url = }} Serotonin 5-HT_2A 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.{{cite journal | vauthors = Duan W, Cao D, Wang S, Cheng J | title = Serotonin 2A Receptor (5-HT_2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants | journal = Chemical Reviews | volume = 124 | issue = 1 | pages = 124–163 | date = January 2024 | pmid = 38033123 | doi = 10.1021/acs.chemrev.3c00375 }}{{cite journal | vauthors = Atiq MA, Baker MR, Voort JL, Vargas MV, Choi DS | title = Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties | journal = Psychopharmacology | volume = | issue = | date = May 2024 | pmid = 38743110 | doi = 10.1007/s00213-024-06599-5 | doi-access = free }}

ITI-1549 has high affinity for the serotonin 5-HT_2A receptor (K_i = 10.2{{nbsp}}nM) and acts as a partial agonist of the β-arrestin pathway with an intrinsic activity of 72% (relative to α-methylserotonin). Conversely, unlike serotonergic psychedelics, ITI-1549 does not activate the G_q pathway. Hence, it is a biased agonist of the serotonin 5-HT_2A receptor. In accordance with the preceding, ITI-1549 does not produce the HTR, a behavioral proxy of psychedelic effects, in animals.{{cite journal | vauthors = Canal CE, Morgan D | title = 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 | journal = Drug Testing and Analysis | volume = 4 | issue = 7-8 | pages = 556–576 | date = 2012 | pmid = 22517680 | pmc = 3722587 | doi = 10.1002/dta.1333 }}{{cite book | vauthors = Kozlenkov A, González-Maeso J | title=The Neuroscience of Hallucinations | chapter=Animal Models and Hallucinogenic Drugs | publisher=Springer New York | publication-place=New York, NY | date=2013 | isbn=978-1-4614-4120-5 | doi=10.1007/978-1-4614-4121-2_14 | page=253–277}} However, similarly to serotonergic psychedelics, ITI-1549 has been found to produce anxiolytic-like and prosocial effects in animals. Antidepressant-like and psychoplastogenic effects of ITI-1549 in animals have yet to be assessed or reported. In any case, various other non-hallucinogenic serotonin 5-HT_2A receptor agonists selective for the β-arrestin pathway have been found to produce antidepressant-like effects in animals.{{cite journal | vauthors = Cao D, Yu J, Wang H, Luo Z, Liu X, He L, Qi J, Fan L, Tang L, Chen Z, Li J, Cheng J, Wang S | title = Structure-based discovery of nonhallucinogenic psychedelic analogs | journal = Science | volume = 375 | issue = 6579 | pages = 403–411 | date = January 2022 | pmid = 35084960 | doi = 10.1126/science.abl8615 }}

In addition to the serotonin 5-HT_2A receptor, ITI-1549 has high affinity for the serotonin 5-HT_2B receptor (K_i = 4.8{{nbsp}}nM). However, it acts as an antagonist of this receptor rather than as an agonist ({{Abbrlink|IC₅₀|half-maximal inhibitory concentration}} = 13.8{{nbsp}}nM). Based on these findings, continuous administration of ITI-1549 is not expected to pose a risk of cardiac valvulopathy. This is in contrast to many serotonergic psychedelics, which have been shown to act as potent serotonin 5-HT_2B receptor agonists.{{cite journal | vauthors = Tagen M, Mantuani D, van Heerden L, Holstein A, Klumpers LE, Knowles R | title = The risk of chronic psychedelic and MDMA microdosing for valvular heart disease | journal = Journal of Psychopharmacology | volume = 37 | issue = 9 | pages = 876–890 | date = September 2023 | pmid = 37572027 | doi = 10.1177/02698811231190865 }}{{cite journal | vauthors = Rouaud A, Calder AE, Hasler G | title = Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: Comparison to known cardiotoxins | journal = Journal of Psychopharmacology | volume = 38 | issue = 3 | pages = 217–224 | date = March 2024 | pmid = 38214279 | pmc = 10944580 | doi = 10.1177/02698811231225609 }} ITI-1549 is additionally a potent agonist of the serotonin 5-HT_2C receptor (K_i = 21{{nbsp}}nM; {{Abbrlink|EC₅₀|half-maximal effective concentration}} = 40{{nbsp}}nM).

The drug is a small molecule, but its chemical structure does not yet seem to have been disclosed. It is said to be chemically unrelated to existing plant-derived and synthetic serotonergic psychedelics. However, its structure was disclosed in a 2024 patent.{{cite patent | country = WO | number = 2024145659 | title=Heterocycle fused gamma-carbolines acting on the serotonine 5-ht2a receptor | url=https://patents.google.com/patent/WO2024145659A1/ | pubdate= 4 July 2024 | assign=Intra-Cellular Therapies, Inc. | inventor = Li P, Davis R, Snyder G, Zhang L, Zheng G , Quai Y, Zhang Q }} 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. It is structurally related to the atypical antipsychotic lumateperone.

As of February 2024, ITI-1549 is in the preclinical stage of development for psychiatric disorders. A phase 1 clinical trial is being planned and is expected to commence in late 2024 or early 2025.{{cite web | title=A study of ITI-1549 | website=AdisInsight | date=28 February 2024 | url=https://adisinsight.springer.com/trials/700371344 | access-date=24 October 2024}} The drug is under development by Intra-Cellular Therapies. ITI-1549 was first described in the scientific literature by 2023.

• List of investigational hallucinogens and entactogens
• List of miscellaneous 5-HT_2A receptor agonists
• BMB-201
• Zalsupindole

{{Reflist}}

{{Serotonin receptor modulators}}

Category:5-HT2A agonists

Category:5-HT2B antagonists

Category:5-HT2C agonists

Category:Biased ligands

Category:Experimental antidepressants

Category:Experimental non-hallucinogens

Category:Experimental psychiatric drugs

Category:Non-hallucinogenic 5-HT2A receptor agonists