LSD-like molecules could treat depression without the psychedelic trip

Scientists from the University of California, San Fransisco, produced compounds that target the same key receptor that LSD activates but do not cause any psychedelic side effects, according to a press release by the institution.

Clinical trials conducted on mice have shown that a single dose produced potent antidepressant and antianxiety effects, lasting up to two weeks.

Fitting into a receptor called 5HT2a

The molecules were designed to bind to a receptor called 5HT2a, the main target of psychedelics like LSD and psilocybin mushrooms. The receptor is also activated by serotonin, a naturally occurring hormone that regulates mood, cognition, and many other functions in the body.

The 5HT2a receptor is thought to play a role in psychotic disorders, such as schizophrenia, anxiety, and depression. Unlike a host of antipsychotic and antidepressant medicines, which block its activity, the new molecules activate it very differently than psychedelics.

Recent studies have already demonstrated that one or two high doses of psychedelics like psilocybin and MDMA can have potent and long-term effects on anxiety and PTSD. However, it is unknown if the trip that comes with these psychedelics has a role in the treatment or if new treatments could be developed without these side effects.

This new study shows the possibility of disentangling these effects. Although it has been known for many years that 5HT2a receptors activate several signaling pathways in cells, there have never been any selective drugs to investigate what each route accomplished.

"The receptors are like antennae. They pick up a chemical signal, and downstream a bunch of things get activated in a cell," said Brian Shoichet, Ph.D., professor of pharmaceutical chemistry at the UCSF School of Pharmacy.

Potent molecules

The initial goal of the research team was not to find molecules that might be used to create new medicines for depression. Their first aim was to discover a method for screening a particular type of compound named tetrahydropyridine, which is challenging to synthesize and is hence missing from virtual libraries while being common among FDA-approved medications.

But Bryan Roth, MD, Ph.D., of UNC-Chapel Hill, thought the molecules might be an interesting way to test the function of the 5HT2b receptor.

“There wasn’t really any sense that drugs like psychedelics that activate this receptor would be therapeutic until psilocybin was tried in clinical trials for depression and shown to have this remarkable effect,” he said. “That really galvanized our interest, which basically started this collaboration.”

Team members had recently solved the crystal structure of the 5HT2b receptor and used that structure to model the 5HT2a until the team worked out the crystal structure of 5HT2a.

The molecules were chosen from a computational library of 75 million candidates. They were synthesized by Jonathan Ellman, Ph.D., the Eugene Higgins Professor of Chemistry and professor of pharmacology at Yale University, and the UCSF, UNC, and Yale team spent almost a year optimizing them.

“The final molecules were 100 times more potent than what we started with,” Shoichet said, although they were still not nearly as strong as LSD. “In the animals, they are very potent, much more potent than Prozac.”

The mice were put through a series of tests by Wetsel's lab to see whether the molecules could ease symptoms similar to those of anxiety and depression. And the results were quite successful.

The research might pave the way for developing novel antidepressants that are more potent and have fewer side effects than the current medicines, which don't work for everyone and require daily intake.

The next aim of the researchers is to optimize the compounds so that they'll be selective enough to be used in clinical trials.

The study was published in the journal Nature.

Abstract:

There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally1,2,3,4. Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines—a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C–H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization5,6,7. Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT2A receptor (5-HT2AR) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT2A or the 5-HT2B receptors. Structure-based optimization led to the 5-HT2AR agonists (R)-69 and (R)-70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HT2AR agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT2AR. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HT2AR agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered.