A recent study published in Science Signaling provides evidence that a newly engineered psychedelic compound can produce antidepressant and anti-anxiety effects in mice without causing gastrointestinal side effects. By altering the chemical structure of an existing psychedelic drug, researchers created a variant that targets specific brain receptors linked to mental health benefits but avoids receptors associated with nausea and physical discomfort.
“Psychedelics such as psilocybin and LSD are showing therapeutic potential for individuals with severe psychiatric conditions, including depression, anxiety and PTSD,” explained study co-authors Javier Gonzรกlez-Maeso, a professor of pharmacology and toxicology at the Virginia Commonwealth University School of Medicine, and Malgorzata Dukat, a professor of medicinal chemistry at the Virginia Commonwealth University School of Pharmacy. “However, like most therapeutic drugs, psychedelics can also produce unwanted side effects.”
โAnother interesting aspect of this field is that essentially all psychedelics currently being studied clinically belong to three major chemical classes: phenethylamines, such as mescaline; tryptamines, such as psilocybin; and ergolines, such as LSD,โ the authors noted. โDespite their chemical differences, many of their hallucinogenic and potentially therapeutic effects are mediated through the serotonin 2A receptor (or 5-HT2A receptor) in the brain, as first proposed by Prof. Richard A. Glennon (coauthor of the manuscript) in 1984.โ
The serotonin 2A receptor mediates positive mood and neural adaptability, but the drugs that target it often lack specificity. โWe became interested in quipazine, a serotonergic compound first described in the 1960s and originally investigated as a potential antidepressant,โ the authors explained. โQuipazine was never developed for routine medical use, in part because it also activates another serotonin receptor, the 5-HT3 receptor, which is highly expressed in the gastrointestinal system and can produce significant gastrointestinal side effects.โ
To separate the therapeutic benefits from adverse physical reactions, the authors sought to chemically redesign quipazine. โOur goal was to combine medicinal chemistry in Dr. Dukatโs laboratory with molecular and behavioral pharmacology in Dr. Maesoโs laboratory to design, synthesize and test new compounds derived from quipazine,โ the researchers said.
โThe Dukat team had already investigated 5-HT2 and 5-HT3 structure-activity relationships and found that quinazolines bind at, but are devoid of, 5-HT3 receptor activation,โ the authors told PsyPost. โWe wanted compounds that retained activity at the 5-HT2A receptor while minimizing activity at the 5-HT3 receptor; hence, investigation of quipazine/quinazoline hybrid molecules. That effort led us to design VCU-1012, a novel quinazoline compound that activates the 5-HT2A receptor while showing minimal activity at the 5-HT3 receptor.โ
The authors synthesized several variations of the quipazine molecule and tested these new compounds on human embryonic kidney cells. When the scientists screened VCU-1012 against a panel of over 40 other receptors, it showed minimal off-target activity. VCU-1012 completely failed to activate the serotonin 3 receptor, indicating it might bypass the physical distress seen with the original drug.
This broad testing approach relied on multiple areas of scientific specialty. โThis study was a highly collaborative effort,โ Gonzรกlez-Maeso and Dukat noted. โIt brought together the medicinal chemistry expertise of Dr. Dukatโs laboratory and the molecular and behavioral pharmacology expertise of the Maeso laboratory, along with important contributions from other teams at VCU. These included the laboratory of Scott Ramsey, which helped characterize effects at the 5-HT3 receptor; the laboratory of Imad Damaj, which contributed expertise in mouse behavioral models, and the laboratory of Hamid Akbarali, which evaluated gastrointestinal motility.โ
To test the physical side effects in a living organism, the researchers evaluated gastrointestinal function in male mice, using six to eight animals per group. They fed the mice a harmless charcoal solution and measured how far the charcoal traveled through the small intestine over a 30-minute period. Mice injected with the original quipazine drug at a dose of 5 milligrams per kilogram of body weight experienced a severe slowdown in digestion. In contrast, mice given VCU-1012 at 1 milligram per kilogram showed normal intestinal movement that was indistinguishable from mice given a plain saline vehicle injection.
Next, the team evaluated behavioral effects by measuring a specific head-twitch behavior in groups of six mice. This rapid side-to-side head movement is a standard animal proxy for hallucinogenic effects. VCU-1012 prompted a robust increase in head twitches within the first 15 minutes of administration, which was completely blocked when mice were pretreated with a drug that selectively prevents serotonin 2A receptor activation.
To evaluate potential antidepressant properties, the researchers used a forced-swim test. Mice were placed in a beaker of water for a short time to induce a passive coping state, which is characterized by floating rather than swimming. Twenty-four hours after receiving VCU-1012, the classical psychedelic psilocybin, or a saline vehicle, the mice were retested. The researchers also performed this test on a separate group of eight to ten genetically modified mice lacking the serotonin 2A receptor.
Both psilocybin and VCU-1012 reduced floating time in normal mice, which suggests an antidepressant-like effect lasting well beyond the drug’s immediate hallucinogenic window. In the genetically modified mice lacking the serotonin 2A receptor, VCU-1012 had no behavioral effect. Psilocybin still reduced floating time in the modified mice, which indicates psilocybin relies on additional biological pathways that VCU-1012 does not engage.
The researchers also explored whether the compound could alleviate anxiety caused by medical treatments. They repeatedly administered the chemotherapy drug paclitaxel to groups of seven or eight mice to induce a prolonged state of anxiety. Anxiety was measured by observing how much time the mice spent in the brightly lit section of a specialized testing box.
Paclitaxel noticeably reduced the time mice spent in the light area. A single dose of VCU-1012 given 24 hours prior restored normal exploratory behavior, countering the chemotherapy-induced anxiety without altering the animals’ general movement levels.
To understand how the drug alters the brain on a microscopic level, the scientists examined dendritic spines. These are tiny protrusions on the branches of brain cells that help form synapses, or connections, with other neurons. The team used a fluorescent virus to visually highlight neurons in the frontal cortex, analyzing 40 to 106 neurons from three or four mice per group.
Both psilocybin and VCU-1012 increased the density of mature, mushroom-shaped dendritic spines 24 hours after a single dose. This change indicates enhanced brain plasticity and stronger neural connections. Just as in the behavioral tests, this structural brain plasticity did not occur in mice lacking the serotonin 2A receptor.
Finally, the researchers used computer modeling and mutated receptor cells to see exactly how VCU-1012 fits into the serotonin 2A receptor. โOne particularly interesting finding came from examining how VCU-1012 interacts with the 5-HT2A receptor,โ the authors observed. โYou can think of the receptorโs binding pocket as a small three-dimensional lock. A drug with the right shape and chemical properties can fit into that lock and change how the receptor behaves.โ
โWe found that VCU-1012 occupies this binding pocket in a different three-dimensional orientation from serotonin, the neurotransmitter that naturally activates the receptor,โ they continued. โThat finding suggests that there may be additional ways to chemically engage the 5-HT2A receptor beyond those used by classical psychedelics. This opens new possibilities for designing chemically distinct classes of psychedelic compounds and investigating how different interactions with the same receptor influence their biological and behavioral effects.โ
The data suggests that VCU-1012 fits into the receptor’s primary binding pocket in a slightly different orientation than the body’s natural serotonin, relying on a specific network of hydrogen bonds. โOur study shows that it is possible to design a psychedelic-like compound from a new chemical class that produces potentially beneficial behavioral and brain-plasticity effects in mice while avoiding an important receptor associated with gastrointestinal side effects,โ the researchers said.
Animal models of anxiety and depression, such as the forced-swim test and the light-dark box, cannot fully capture the complexity of human psychiatric disorders. A mouse’s physical responses do not perfectly translate to the subjective emotional experiences or hallucinogenic trips reported by humans. The therapeutic efficacy observed in these experiments might not completely predict actual clinical outcomes in human patients.
โThese findings are preclinical, and VCU-1012 is not ready for use in humans,โ the authors noted. โAlthough we were able to greatly reduce its activity at the 5-HT3 receptor, VCU-1012 still interacts with other receptors, including the 5-HT2B receptor. Activation of this receptor can be associated with peripheral side effects, including cardiac valvulopathy.โ
Because cardiac valvulopathy involves damage to the heart’s valves, avoiding this off-target receptor is an important safety consideration. โTherefore, additional medicinal chemistry will be necessary to improve the selectivity and safety profile of this new class of compounds before considering clinical development,โ they added. All behavioral and neurological tests in this study were conducted exclusively on male mice. Because biological sex often influences how bodies process drugs, future research will need to include female animals to determine if these effects apply universally.
โOne major goal is to conduct additional structure-activity relationship studies to design compounds with greater selectivity for the 5-HT2A receptor and fewer off-target effects,โ the authors explained. They also hope to answer fundamental questions about how these drugs work. โA broader question we hope to address is whether the hallucinogenic effects produced by classical psychedelics, and by compounds such as VCU-1012, are necessary for their potentially beneficial effects on behavior and brain plasticity.โ
โUnderstanding whether these properties can be separated could help guide the development of the next generation of psychedelic-inspired therapeutics,โ they concluded. โThe study illustrates how combining medicinal chemistry, molecular pharmacology and animal models can help us understand how psychedelic drugs work and, ultimately, guide the design of compounds with improved therapeutic and safety profiles.โ
The study, โDesign of a new psychedelic quipazine analog with therapeutic efficacy and potentially fewer side effects,โ was authored by Jason Younkin, Ajay H. Bansode, Somdatta Saha, Archana Paymode, Jessica L. Maltman, Charles B. Jones, Justin M. Silverman, Belle Buzzi, Alaina M. Jaster, Michael Fiorillo, Jeremy Rolquin, George D. Miller, Roya Abedi, Minho Kang, Maya Gaines-Smith, Enrique I. Valenzuela Lesme, Mattias Embretsen, Jennifer T. Wolstenholme, Richard A. Glennon, Hamid I. Akbarali, M. Imad Damaj, I. Scott Ramsey, Maลgorzata Dukat, and Javier Gonzรกlez-Maeso.