Abstract
Provided herein are novel azepinoindoles as 5-HT2C agonists, pharmaceutical compositions, use of such compounds in treating depression, drug addiction, alcoholism, post-traumatic stress disorder (PTSD), and neuropathic pain, and processes for preparing such compounds.
Important Compound Classes
Title
Azepinoindoles and Methods of Preparation Thereof
Patent Publication Number
WO 2023/212811 A1
URL
Publication Date
November 9, 2023
Priority Application
US 63/338,889
Priority Date
May 6, 2022
Inventors
Kozikowski, A.; Tueckmantel, W.
Assignee Company
Bright Minds Biosciences Inc., Canada
Disease Area
Depression, drug addiction, alcoholism, post-traumatic stress disorder (PTSD), and neuropathic pain
Biological Target
5-HT2C
Summary
Psilocybin is a naturally occurring psychedelic compound produced by more than 200 species of mushrooms collectively known as “psilocybin mushrooms.” As a prodrug, psilocybin is quickly metabolized by the body to generate the bioactive psilocin, which has mind altering effects not unlike those produced by other psychedelics such as lysergic acid diethylamide (LSD), mescaline, and N,N-dimethyltryptamine (DMT). These effects include, inter alia, euphoria, visual and mental hallucinations, changes in perception, and distortions in one’s sense of time.
Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. After the discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD) and the identification of serotonin in the brain, early research focused intensively on LSD. Today, there is consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A (5-HT2A) receptors. Psychedelics have both rapid onset and persisting effects, which includes changes in mood and brain function. The classical psychotic agents include LSD, psilocybin, or mescaline.
The 5-HT2A receptor plays an important role in emotional responses and is an important target to be considered in the action of 5-HT2A agonist psychedelics. In fact, a majority of known 5-HT2A agonists produce hallucinogenic effects in humans. Psilocybin activates 5HT1A receptors, which may contribute to antidepressant/antianxiety effects.
The present application describes a series of novel azepinoindoles as 5-HT2C agonists for the treatment of depression, drug addiction, alcoholism, post-traumatic stress disorder (PTSD) and neuropathic pain. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.
Definitions
R1 = H, C1–C6 alkyl, C1–C6 substituted alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3–C6 cycloalkyl, (C3–C6 cycloalkyl)(C1–C6 alkyl), C3–C6 heterocyclyl, (C3–C6 heterocyclyl)(C1–C6 alkyl), aryl(C1–C6 alkyl) and heteroaryl(C1–C6 alkyl);
R2 = C1–C6 alkyl, C1–C6 substituted alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3–C6 cycloalkyl, (C3–C6 cycloalkyl)(C1–C6 alkyl), C3–C6 heterocyclyl, (C3–C6 heterocyclyl)(C1–C6 alkyl), aryl(C1–C6 alkyl), heteroaryl, heteroaryl(C1–C6 alkyl), CN, CONH2, and halogen;
R3 = H, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3–C6 cycloalkyl, (C3–C6 cycloalkyl)(C1–C6 alkyl), aryl(C1–C6 alkyl), acetyl, and heteroaryl(C1–C6 alkyl);
a = H, halogen, lower alkyl, CHF2, CF3, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, amine, and cyano;
b = H, halogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, amine, and cyano;
c1 and c2 together form a part of a spiro-fused cyclopropane or cyclobutene ring;
d1 and d2 together form a part of a spiro-fused cyclopropane or cyclobutene ring;
e1 and e2 together form a part of a spiro-fused cyclopropane or cyclobutene ring
f1 and f2 together form a part of a spiro-fused cyclopropane or cyclobutene ring; and
Z = H, R5, (R6)(R7)N–C(O)-, C1–C6 alkyl–C(O), C3–C6 cycloalkyl–C(O), aryl–C(O), and heteroaryl–C(O).
Key Structures
Biological Assay
The 5-HT2C receptor BRET Ca2+ flux functional assay was performed. The compounds described in this application were tested for agonist activity at 5-HT2C receptor. The 5-HT2C EC50 (nM) values are shown in the following Table.
Biological Data
The Table below shows representative
compounds that were tested for agonist activity at 5-HT2C. The biological
data obtained from testing representative examples are listed in the
following Table.
Claims
Total claims: 16
Compound claims: 10
Method of treatment claims: 4
Use of compound claims: 2
Recent Review Articles
See References − .
The author declares no competing financial interest.
Published as part of ACS Medicinal Chemistry Letters special issue “Psychedelics and Entactogens”.
References
- Cummins B. R., Billac G. B., Nichols D. E., Nichols C. D.. 5-HT2A receptors: Pharmacology and functional selectivity. Pharmacol. Rev. 2025;77:100059. doi: 10.1016/j.pharmr.2025.100059. [DOI] [PubMed] [Google Scholar]
- Miranda L.. Antidepressant and anxiolytic effects of activating 5-HT2A receptors in the anterior cingulate cortex and the theoretical mechanisms underlying them - A scoping review of available literature. Brain Res. 2025;1846:149226. doi: 10.1016/j.brainres.2024.149226. [DOI] [PubMed] [Google Scholar]
- Gonzalez L., Bezzi P.. Astrocyte dysfunctions in obsessive compulsive disorder: Rethinking neurobiology and therapeutic targets. J. Neurochem. 2025;169:e70092. doi: 10.1111/jnc.70092. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schimmelpfennig J., Jankowiak-Siuda K.. Exploring DMT: Endogenous role and therapeutic potential. Neuropharmacology. 2025;268:110314. doi: 10.1016/j.neuropharm.2025.110314. [DOI] [PubMed] [Google Scholar]
- Sabnis R. W.. Novel desamide isotryptamine tetracycles as 5-HT2C agonists for treating brain disorders. ACS Med. Chem. Lett. 2025;16:976–977. doi: 10.1021/acsmedchemlett.5c00286. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weiss F., Magnesa A., Gambini M., Gurrieri R., Annuzzi E., Elefante C., Perugi G., Marazziti D.. Psychedelic-induced neural plasticity: A comprehensive review and a discussion of clinical implications. Brain Sci. 2025;15:117. doi: 10.3390/brainsci15020117. [DOI] [PMC free article] [PubMed] [Google Scholar]