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"Psychedelic drugs hold great promise for treating mental health conditions like depression and anxiety. But beyond their otherworldly hallucinogenic manifestations, many of these drugs also come with all-too-familiar side effects like nausea, vomiting, and gastrointestinal discomfort.
This occurs because the psychedelic compounds activate several off-target pathways as well as the intended serotonin receptors in the brain.
Reducing these unwanted interactions and the unpleasant symptoms that come with them is an important step for demonstrating the safety of psychedelics.
In a new study ... researchers pushed closer to this reality by re-engineering the synthetic psychedelic drug quipazine to activate only the desired receptors .
The pharmacologists began by examining quipazine atom-by-atom to identify how the drug could bind to both the target 5-HT2AR receptor and the 5-HT3R receptor that causes nausea and other gastrointestinal symptoms.
After singling out the nitrogen atom responsible, they replaced it and rearranged the whole molecule. The resultant drug could still bind to the desired 5-HT2AR receptor, but it bounced off 5-HT3R receptors.
To test the new psychedelic’s effectiveness, the researchers gave the drug to mice with symptoms of depression and anxiety. Once the hallucinogenic effects subsided, the mice exhibited fewer symptoms and showed no apparent discomfort. When they examined the animals’ brains, the researchers found an increased density of neuron structures called dendritic spines, a telltale sign that the psychedelic had restored some of the brain activity lost to depression. ..."
From the editor's summary and abstract:
"Editor’s summary
The clinical use of serotonergic psychedelics is limited by their side effects. Younkin et al. generated a derivative (called VCU-1012) of the psychedelic quipazine with greater activity at the serotonin receptor subtype that mediates the clinically desirable effects (5-HT2AR) than at the serotonin receptor subtype responsible for the undesirable ones.
Similar to quipazine, VCU-1012 exerted antidepressant and antianxiolytic effects in mice but without the gastrointestinal side effects of quipazine. Moreover, like other psychedelics, VCU-1012 increased dendritic spine density in the frontal cortex in a 5-HT2AR–dependent manner.
Thus, VCU-1012 shows promise as a 5-HT2AR agonist with a more favorable side effect profile than those of typical psychedelics. ...
Abstract
Psychedelics that target serotonin 2A receptors (5-HT2ARs) hold therapeutic promise for neuropsychiatric disorders but are often hindered by off-target actions. The 5-HT2AR agonist quipazine also activates 5-HT3R, which contributes to undesirable side effects.
Here, we developed VCU-1012, a quipazine-based, structurally distinct 5-HT2AR agonist devoid of 5-HT3R activity.
VCU-1012 was developed by applying a strategic chemical design that combined deconstruction to pinpoint the nitrogen atom critical for 5-HT2AR activation with structure-activity relationship studies to minimize 5-HT3R agonism.
We showed that VCU-1012 modulated dendritic spine structural plasticity in the frontal cortex and produced antidepressant-like effects in mice through 5-HT2AR without activating 5-HT3R, thereby avoiding the gastrointestinal side effects of quipazine.
In addition, our molecular modeling and mutant analysis suggested that VCU-1012 interacted in the canonical orthosteric binding pocket of 5-HT2AR.
Together, these findings establish VCU-1012 as a potential therapeutic agent with reduced gastrointestinal impact, emphasize how differences in ligand-receptor interactions influence ligand positioning in the receptor binding pocket, and provide guidance for designing psychedelics with targeted therapeutic benefits."
Design of a new psychedelic quipazine analog with therapeutic efficacy and potentially fewer side effects (no public access)
Design and Synthesis of Quipazine Analogs for Programmable Control of Psychedelic Effects (A PhD thesis covering a similar topic. The author was not part of the team authoring the above research article.)
VCU-1012 (Wikipedia page indicating this psychedelic drug was already developed in 2024)
VCU-1012 2D chemical structure
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