ITI-1549 is a putatively non-

hallucinogen Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mo ...

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

5-HT_2A receptor

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

which is under development for the treatment of

mood disorder A mood disorder, also known as an affective disorder, is any of a group of conditions of mental and behavioral disorder where the main underlying characteristic is a disturbance in the person's mood. The classification is in the ''Diagnostic ...

s and other

psychiatric disorder A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...

s. In addition to acting at the serotonin 5-HT_2A receptor, it is also an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.5-HT_2B receptor and an agonist of the serotonin 5-HT_2C receptor. The drug's

route of administration In pharmacology and toxicology, a route of administration is the way by which a medication, drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance ...

has not been specified.

Pharmacology

Pharmacodynamics

Serotonergic psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

s like

psilocybin Psilocybin, also known as 4-phosphoryloxy-''N'',''N''-dimethyltryptamine (4-PO-DMT), is a natural product, naturally occurring tryptamine alkaloid and Investigational New Drug, investigational drug found in more than List of psilocybin mushroom ...

and

lysergic acid diethylamide Lysergic acid diethylamide, commonly known as LSD (from German ; often referred to as acid or lucy), is a Semisynthesis, semisynthetic, Hallucinogen, hallucinogenic compound derived from ergot, known for its powerful psychological effects and ...

(LSD) are

s of the

5-HT_2A receptor that activate both the

β-arrestin Arrestins (abbreviated Arr) are a small family of proteins important for regulating signal transduction at G protein-coupled receptors. Arrestins were first discovered in the late '80s as a part of a conserved two-step mechanism for regulatin ...

and G_q

signaling pathway In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukary ...

s. 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 The head-twitch response (HTR), also sometimes known as wet dog shakes (WDS) in rats, is a rapid side-to-side head movement that occurs in mice and rats in association with serotonin 5-HT2A receptor activation. Serotonergic psychedelics like lys ...

(HTR), in animals. Serotonin 5-HT_2A receptor agonists are of interest for the potential treatment of psychiatric disorders like depression and

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

, but the hallucinogenic effects of serotonergic psychedelics serve as a barrier and partial limiting factor in this regard. ITI-1549 has high

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the serotonin 5-HT_2A receptor (K_i = 10.2nM) and acts as a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of the β-arrestin pathway with an

intrinsic activity Intrinsic activity (IA) and efficacy (Emax) refer to the relative ability of a drug- receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind ...

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 Functional selectivity (or agonist trafficking, biased agonism, biased signaling, ligand bias, and differential engagement) is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand (often the end ...

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. However, similarly to serotonergic psychedelics, ITI-1549 has been found to produce

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

-like and

prosocial Prosocial behavior is a social behavior that "benefit other people or society as a whole", "such as helping, sharing, donating, co-operating, and volunteering". The person may or may not intend to benefit others; the behavior's prosocial benefi ...

effects in animals.

Antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

-like and

psychoplastogen Psychoplastogens, also known as neuroplastogens, are a group of Small molecule#Drugs, small molecule drugs that produce rapid and sustained effects on neuronal structure and function, intended to manifest therapeutic benefit after a single admin ...

ic 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. In addition to the serotonin 5-HT_2A receptor, ITI-1549 has high affinity for the serotonin 5-HT_2B receptor (K_i = 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 Cardiac fibrosis commonly refers to the excess deposition of extracellular matrix in the cardiac muscle, but the term may also refer to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts. Fibrotic c ...

. This is in contrast to many serotonergic psychedelics, which have been shown to act as potent serotonin 5-HT_2B receptor agonists. ITI-1549 is additionally a potent agonist of the serotonin 5-HT_2C receptor (K_i = 21nM; = 40nM).

Chemistry

The chemical structure was disclosed in a 2024

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an sufficiency of disclosure, enabling discl ...

. 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 soxazol-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 The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as tranquilizers and neurol ...

lumateperone Lumateperone, sold under the brand name Caplyta, is an atypical antipsychotic medication of the butyrophenone class. It is approved for the treatment of schizophrenia as well as bipolar depression, as either monotherapy or adjunctive therapy ...

Clinical trials

As of February 2024, ITI-1549 is in the preclinical stage of development for psychiatric disorders. A phase 1

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

is being planned and is expected to commence in late 2024 or early 2025. The drug is under development by Intra-Cellular Therapies. ITI-1549 was first described in the

scientific literature Scientific literature encompasses a vast body of academic papers that spans various disciplines within the natural and social sciences. It primarily consists of academic papers that present original empirical research and theoretical ...

by 2023.

References

{{Serotonin receptor modulators 5-HT2A agonists 5-HT2B antagonists 5-HT2C agonists Biased ligands Experimental antidepressants Experimental non-hallucinogens Experimental psychiatric drugs Non-hallucinogenic 5-HT2A receptor agonists

Pharmacology

Pharmacodynamics

Chemistry

Clinical trials

See also

References