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ITI-1549
Non-hallucinogenic 5-HT2A agonist From Wikipedia, the free encyclopedia
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ITI-1549 is a putatively non-hallucinogenic serotonin 5-HT2A receptor agonist of the pyridopyrroloquinoxaline family which is under development for the treatment of mood disorders and other psychiatric disorders.[1][4][5][2][3] 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.[3][6] The drug's route of administration has not been specified.[1]
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Pharmacology
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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.[3] 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.[3][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).[3] Conversely, unlike serotonergic psychedelics, ITI-1549 does not activate the Gq pathway.[3] Hence, it is a biased 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 produce anxiolytic-like and prosocial effects in animals.[3] Antidepressant-like and psychoplastogenic 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 serotonin 5-HT2B receptor (Ki = 4.8 nM).[3] However, it acts as an antagonist of this receptor rather than as an agonist (IC50 = 13.8 nM).[3] Based on these findings, continuous administration of ITI-1549 is not expected to pose a risk of cardiac valvulopathy.[3] 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]
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Chemistry
The chemical structure was disclosed in a 2024 patent.[6] It is a pyridopyrroloquinoxaline derivative and 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][4][2] 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][4][2] ITI-1549 was first described in the scientific literature by 2023.[3]
See also
References
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