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. 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. The drug's route of administration has not been specified.

Interactions

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. 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. 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.

ITI-1549 has high affinity for the serotonin 5-HT2A receptor (Ki = 10.2nM) 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 Gq pathway. Hence, it is a biased agonist of the serotonin 5-HT2A receptor. In accordance with the preceding, ITI-1549 does not produce the HTR, a behavioral proxy of psychedelic effects, in animals. 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-HT2A receptor agonists selective for the β-arrestin pathway have been found to produce antidepressant-like effects in animals.

In addition to the serotonin 5-HT2A receptor, ITI-1549 has high affinity for the serotonin 5-HT2B receptor (Ki = 4.8nM). However, it acts as an antagonist of this receptor rather than as an agonist ( = 13.8nM). 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-HT2B receptor agonists. ITI-1549 is additionally a potent agonist of the serotonin 5-HT2C receptor (Ki = 21nM; = 40nM).

Chemistry The chemical structure was disclosed in a 2024 patent. 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 a pyridopyrroloquinoxaline derivative and is structurally related to the atypical antipsychotic lumateperone.

History ITI-1549 was first described in the scientific literature by 2023.

Research As of February 2024, ITI-1549 is in the preclinical research stage of development for treatment of psychiatric disorders. A phase 1 clinical trial is being planned and is expected to commence in late 2024 or early 2025. The drug is under development by Intra-Cellular Therapies.

See also Pyridopyrroloquinoxaline List of investigational hallucinogens and entactogens List of miscellaneous 5-HT2A receptor agonists Non-hallucinogenic 5-HT2A receptor agonist

References

External links ITI-1549 - Isomer Design