Re-engineered psychedelic drug retains therapeutic activity in mice, while limiting negative side effects

A redesigned psychedelic compound retains therapeutic activity while limiting unwanted side-effects during testing on mice. The molecule’s structure was adjusted to avoid interactions with a specific subset of serotonin receptors, potentially offering a blueprint for safer neuropsychiatric drugs.

Some psychedelic drugs have shown potential in the treatment of mental health conditions like depression, anxiety and post-traumatic stress disorder. Although they are best known for their hallucinogenic effects, psychedelics can also trigger nausea and gastrointestinal discomfort by activating serotonin receptors outside the brain. Reducing unpleasant symptoms is, therefore, a critical step for improving the safety of psychedelics in the clinic.

A team from Virginia Commonwealth University, US, led by Małgorzata Dukat and Javier González-Maeso has now demonstrated one way of doing this by re-engineering the psychedelic drug, quipazine. ‘Our main goal was to design a quipazine-related compound with properties targeting the serotonin 2A receptor, but without quipazine’s unwanted side effects via the serotonin 3 receptor, whose activation is associated with nausea,’ explains Dukat.

The team systematically deconstructed quipazine, removing and modifying different structural features to determine how each contributed to receptor binding. ‘In medicinal chemistry, “deconstruction” is defined as a process whereby certain molecular features of an agent of interest are removed to determine their influence on drug action,’ notes Dukat.

Quipazine has three nitrogen atoms in its structure. ‘We identified the one responsible for binding the serotonin 2A receptor’, says González-Maeso. ‘Prof Dukat and her team had previously investigated the serotonin 3 receptor action and structure–activity relationships of various compounds and how their structural alteration influenced receptor binding,’ he explains. Drawing on these studies, the researchers replaced quipazine’s quinoline core with a quinazoline unit that features an additional nitrogen atom. The redesigned molecule, which the researchers call VCU-1012, preserved the quipazine-like affinity for the serotonin 2A reception while eliminating activity at the serotonin 3 receptor.

‘This stepwise movement from deconstructing the parent ligand to rebuilding a compound with a more favourable pharmacological profile was the study’s most distinctive feature,’ comments Taufiq Rahman, a pharmacologist at the University of Cambridge, UK, who was not involved in the work.

In mice showing anxiety and depression-linked behaviours, VCU-1012 produced antidepressant-like effects without altering gastrointestinal function. It also increased the density of neuron structures called dendritic spines in the brain’s frontal cortex – a hallmark of the enhanced neural plasticity thought to underlie the long-lasting therapeutic effects of psychedelics.

While the drug remains at an early preclinical stage, González-Maeso believes that the work extends beyond a single drug candidate. ‘This may open a new line of research for the design, synthesis and testing of structurally novel psychedelics with improved therapeutic efficacy and fewer side effects’, he says.