ITI-1549

Clinical data
Other names	ITI1549
Routes of administration	Unspecified[1]
Drug class	Non-hallucinogenic serotonin 5-HT2A receptor agonist[2][3]
Chemical and physical data
Formula	C25H28N4O
Molar mass	400.526 g·mol−1
3D model (JSmol)	Interactive image
SMILES CN1c2cccc3c2N(CC21CC2)[C@H]1CCN(C[C@H]13)CCc1noc2ccccc21

ITI-1549 is a putatively non-hallucinogenic serotonin 5-HT_2A receptor agonist 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-HT_2A receptor, it is also an antagonist of the serotonin 5-HT_2B receptor and an agonist of the serotonin 5-HT_2C receptor.^[3][6] The drug's route of administration has not been specified.^[1]

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.^[3] 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.^[3][7][8][9] 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.^[10][11]

ITI-1549 has high affinity for the serotonin 5-HT_2A receptor (K_i = 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 G_q pathway.^[3] Hence, it is a biased agonist of the serotonin 5-HT_2A 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-HT_2A 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-HT_2A receptor, ITI-1549 has high affinity for the serotonin 5-HT_2B receptor (K_i = 4.8 nM).^[3] However, it acts as an antagonist of this receptor rather than as an agonist (IC₅₀Tooltip half-maximal inhibitory concentration = 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-HT_2B receptor agonists.^[15][16] ITI-1549 is additionally a potent agonist of the serotonin 5-HT_2C receptor (K_i = 21 nM; EC₅₀Tooltip half-maximal effective concentration = 40 nM).^[6]

The drug is a small molecule, but its chemical structure does not yet seem to have been disclosed.^[1][4] It is said to be chemically unrelated to existing plant-derived and synthetic serotonergic psychedelics.^[3] However, its structure was disclosed in a 2024 patent.^[6] It is structurally related to the atypical antipsychotic lumateperone.^[6]

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]

• List of investigational hallucinogens and entactogens
• List of miscellaneous 5-HT_2A receptor agonists
• AAZ-A-154 (DLX-001)
• BMB-201