ITI-1549 has highaffinity for the serotonin 5-HT2A receptor (Ki = 10.2nM) and acts as apartial agonist of the β-arrestin pathway with anintrinsic activity of 72% (relative toα-methylserotonin).[3] Conversely, unlike serotonergic psychedelics, ITI-1549 does not activate the Gq pathway.[3] Hence, it is abiased agonist of the serotonin 5-HT2A receptor.[3] In accordance with the preceding, ITI-1549 does not produce the HTR, a behavioral proxy of psychedelic effects, in animals.[3][12][13] However, similarly to serotonergic psychedelics, ITI-1549 has been found to produceanxiolytic-like andprosocial effects in animals.[3]Antidepressant-like andpsychoplastogenic effects of ITI-1549 in animals have yet to be assessed or reported.[3] 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 serotonin5-HT2B receptor (Ki = 4.8nM).[3] However, it acts as an antagonist of this receptor rather than as an agonist (IC50Tooltip half-maximal inhibitory concentration = 13.8nM).[3] Based on these findings, continuous administration of ITI-1549 is not expected to pose a risk ofcardiac valvulopathy.[3] This is in contrast to many serotonergic psychedelics, which have been shown to act aspotent serotonin 5-HT2B receptor agonists.[15][16] ITI-1549 is additionally a potent agonist of the serotonin5-HT2C receptor (Ki = 21nM;EC50Tooltip half-maximal effective concentration = 40nM).[6]
^abcde"ITI 1549".AdisInsight. 15 January 2024. Retrieved23 October 2024.
^abcdIntra-Cellular Therapies (22 February 2024)."Intra-Cellular Therapies Reports Fourth Quarter And Full-Year 2023 Financial Results And Provides Corporate Update".GlobeNewswire News Room. Retrieved23 October 2024.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.
^"Pipeline".Intracellular Therapies. Retrieved23 October 2024.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.
^abcdWO 2024145659, 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", published 4 July 2024, assigned to Intra-Cellular Therapies, Inc. 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.
^abChisamore N, Kaczmarek E, Le GH, Wong S, Orsini DK, Mansur R, et al. (26 April 2024). "Neurobiology of the Antidepressant Effects of Serotonergic Psychedelics: A Narrative Review".Current Treatment Options in Psychiatry.11 (2). Springer Science and Business Media LLC:90–105.doi:10.1007/s40501-024-00319-8.ISSN2196-3061.
^Kozlenkov A, González-Maeso J (2013). "Animal Models and Hallucinogenic Drugs".The Neuroscience of Hallucinations. New York, NY: Springer New York. pp. 253–277.doi:10.1007/978-1-4614-4121-2_14.ISBN978-1-4614-4120-5.
^Tagen M, Mantuani D, van Heerden L, Holstein A, Klumpers LE, Knowles R (September 2023). "The risk of chronic psychedelic and MDMA microdosing for valvular heart disease".Journal of Psychopharmacology.37 (9):876–890.doi:10.1177/02698811231190865.PMID37572027.
