Structure-activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT receptor agonist. CYB210010 exhibited high agonist potency at 5-HT and 5-HT receptors, modest selectivity over 5-HT, 5-HT, 5-HT, and adrenergic α receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.1-3 mg/kg) elicited a head-twitch response (HTR) and could be administered subchronically at threshold doses without behavioral tolerance. CYB210010 was orally bioavailable in three species, readily and preferentially crossed into the CNS, engaged frontal cortex 5-HT receptors, and increased the expression of genes involved in neuroplasticity in the frontal cortex. CYB210010 represents a new tool molecule for investigating the therapeutic potential of 5-HT receptor activation. In addition, several other compounds with high 5-HT receptor potency, yet with little or no HTR activity, were discovered, providing the groundwork for the development of nonpsychedelic 5-HT receptor ligands.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.3c01961 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Design of Small Non-Peptidic Ligands That Alter Heteromerization between Cannabinoid CB and Serotonin 5HT Receptors.
J Med Chem
December 2024
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona 08028, Spain.
Activation of cannabinoid CB receptors (CBR) by agonists induces analgesia but also induces cognitive impairment through the heteromer formed between CBR and the serotonin 5HT receptor (5HTR). This side effect poses a serious drawback in the therapeutic use of cannabis for pain alleviation. Peptides designed from the transmembrane helices of CBR, which are predicted to bind 5HTR and alter the stability of the CBR-5HTR heteromer, have been shown to avert CBR agonist-induced cognitive impairment while preserving analgesia.
View Article and Find Full Text PDFChronic cannabidiol administration modulates depressive and cognitive alterations induced by social isolation in male mice.
Behav Brain Res
December 2024
Department of Biological Sciences, Laboratory of Neurobiology and Biomaterials (LNBio), Federal University of Ouro Preto, Ouro Preto, Brazil. Electronic address:
Cannabidiol (CBD), a non-psychotropic compound derived from Cannabis sativa, is known for its potential therapeutic effects on central nervous system (CNS) disorders. This study investigates the effects of chronic CBD administration on depressive and cognitive alterations induced by social isolation in male C57BL/6 mice. The experimental design involved adult mice subjected to either group housing or 12 weeks of social isolation.
View Article and Find Full Text PDFMajor depressive disorder (MDD) is one of the most common diseases affecting millions of people worldwide. The use of existing antidepressants in many cases does not allow achieving stable remission, probably due to insufficient understanding of pathological mechanisms. This indicates the need for the development of more effective drugs based on in-depth understanding of MDD's pathophysiology.
View Article and Find Full Text PDFThe antidepressant-like activity of ketamine in the rat chronic mild stress model requires activation of cortical 5-HT1A receptors.
Behav Pharmacol
December 2024
Neurolixis SAS, Castres, France.
Ketamine displays efficacious rapid-acting antidepressant (RAAD) activity in the rat chronic mild stress (CMS) model. It rapidly reverses anhedonia (CMS-induced sucrose consumption deficit) and attenuates working memory deficit (novel object recognition: NOR) following both systemic (intraperitoneal, i.p.
View Article and Find Full Text PDFThe Use of Classic Psychedelics for Depressive and Anxiety-Spectrum Disorders: A Comprehensive Review.
J Clin Psychopharmacol
December 2024
From the Albert Einstein College of Medicine, Bronx, NY.
Following a decades-long decline in psychedelic research resulting from social, political, and legislative factors, there has been greatly renewed interest in these compounds' ability to treat psychiatric disorders. Classic psychedelics, encompassing both natural and synthetic psychoactive compounds, are characterized by their action as agonists or partial agonists of serotonin 5-hydroxytryptamine 2A receptors. In this comprehensive review, we summarize the latest clinical trials of classic psychedelics on depression and anxiety, attending to the patient demographics and methodology of each study.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!