Researchers have designed compounds that hit the same key receptor that LSD activates without causing hallucinations, according to an article (“Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity”) in Nature. A single dose produced antidepressant and antianxiety effects in mice that lasted up to two weeks.

The study may offer a way to develop new kinds of antidepressants that are more effective and have fewer side effects than current medications, which don’t work for many patients and must be taken every day. It represents the culmination of half a dozen years of work by a team that began at UC San Francisco (UCSF), UNC-Chapel Hill, and Yale, and later expanded to Duke and Stanford universities.

“There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally. 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,” wrote the investigators.

“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 derivatization. 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 signaling kinetics that differ from psychedelic 5-HT2AR agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT2AR. The favorable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioral assays.

No psychedelic activity

“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.”

The compounds were designed to fit into the 5HT2a receptor, which is 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 schizophrenia and other psychotic disorders, as well as anxiety and depression, and a host of antipsychotic and antidepressant drugs block its activity. The new molecules activate it, but in a different way than psychedelics.

Recent studies have found that when given in combination with psychotherapy, one or two high doses of psychedelics like psilocybin and MDMA can have significant long-term effects on depression, anxiety, and PTSD. It’s not known if the trip is essential to the treatment, or if drugs could be developed that alleviate symptoms without it.

The current study offers the possibility of disentangling these effects. Although it’s been known for several decades that 5HT2a receptors activate different signaling pathways in cells, until now there were no compounds selective enough to see what each pathway did.

The scientific team discovered the receptors could set off two different pathways, a hallucinatory pathway and an antidepressant/antianxiety one. LSD activates the first one more, while the new compounds activate the second one more.

“The receptors are like antennae,” said Brian Shoichet, PhD, professor of pharmaceutical chemistry at the UCSF School of Pharmacy. “They pick up a chemical signal, and downstream a bunch of things get activated in a cell. The final molecules were 100 times more potent than what we started with,” although not nearly as strong as LSD. “In the animals they are potent, much more potent than Prozac,” he added.

The team’s next project will be optimizing the compounds, making them selective enough to be used in clinical trials. The approach has been patented by Yale, UNC-Chapel Hill, and UCSF and licensed to Onsero, a Boston startup.