Abstract
Provided herein are novel compounds as 5-HT2A agonists, pharmaceutical compositions, use of such compounds in treating depression, and processes for preparing such compounds.
Important Compound Classes
Title
5-HT2A Agonists for Use in Treatment of Depression
Patent Publication Number
US 11633390 B2
URL
Publication Date
April 25, 2023
Priority Application
US 17/090,457
Priority Date
November 5, 2020
Inventors
Kristensen, J. L.; Jensen, A. A.; Marcher-Rorsted, E.; Leth-Petersen, S.
Assignee Company
LOPHORA APS, Denmark
Disease Area
Depression
Biological Target
5-HT2A
Summary
Depression was for a long time considered an illuness of the soul, but it is currently viewed as a disorder of the brain. Norepinephrine and serotonin (5-hydroxytryptamine, 5-HT) act as neurotransmitters in the brain. Serotonin is involved in and regulates diverse biological functions in the brain such as mood, emotion, and sleep. Thus, the serotonergic system and serotonin receptors have been investigated for the treatment of depression and psychiatric disorders.
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 compounds as 5-HT2A agonists for the treatment of depression. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.
Definitions
X = F, Cl, Br, I, CN, S-(C1-C5 alkyl), S-(C1-C5 fluoroalkyl), S-(C2-C5 alkenyl), S-(C2-C5 fluoroalkenyl), S-(C2-C5 alkynyl), S-(C2-C5 fluoroalkynyl), C1-C5 alkyl, C1-C5 fluoroalkyl, C2-C5 alkenyl, C2-C5 fluoroalkenyl, C2-C5 alkynyl and C2-C5 fluoroalkynyl;
Y1 and Y2 = H, O, S, C1-C5 alkyl, C1-C5 fluoroalkyl, and halogen;
R1 is not present when Y1 is H, C1-C3 alkyl, C1-C3 fluoroalkyl, or halogen;
R2 is not present when Y2 is H, C1-C3 alkyl, C1-C3 fluoroalkyl, or halogen;
R3 = F, C1-C3 alkyl, C1-C3 fluoroalkyl, C2-C3 alkenyl, and C2-C3 alkynyl; R4 = H or CH3; and
z = 0, 1, 2, or 3.
Key Structures
Biological Assay
Human 5-HT2A receptor Ca2+/Fluo-4 assay was performed. The compounds described in this application were tested for agonist activity at the 5-HT2A receptor. The 5-HT2A 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-HT2A. The biological
data obtained from testing representative examples are listed in the
following Table.
Claims
Total claims: 15
Method of treatment claims: 15
Recent Review Articles
See refs − .
The author declares no competing financial interest.
Published as part of ACS Medicinal Chemistry Letters special issue “Psychedelics and Entactogens”.
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