Researchers develop a non-psychedelic compound with the same effect as antidepressants

Although most narcotic substances are addictive, it is a remedy for the treatment of some diseases such as depression, anxiety, and ADHD.

Researchers at UNC-Chapel Hill, UC San Francisco, Yale, Duke, and Stanford try to create a non-psychedelic compound with the same antidepressant effect. The study aims to help prevent people from addiction.

Published in Nature on September 28, the study demonstrates that it is possible to develop a substance that directly targets the 5-HT2A serotonin receptors on the surface of particular neurons, the same target that psychedelic medications do, but without producing the same psychedelic effects.

"We were very surprised the compound had any antidepressant activity similar to ketamine and psilocybin, both rapidly acting antidepressant psychedelic drugs," said co-senior author Dr. Bryan L. Roth, the Michael Hooker Distinguished Professor of Pharmacology at the UNC School of Medicine and director of the NIMH Psychoactive Drug Screening Program in the statement of UNC.

"We were basically running a chemistry experiment to see if we could create a compound to activate 5-HT2A."

Yale, UNC-Chapel Hill, and UCSF jointly own the patent for the substance, which they have leased to Onsero, a business established to improve investigational drugs before they are put through.

"We don't know if we'll see the same effects in people," Roth said. "But we hope to find out. It would be a game changer to create a one-dose, long-acting therapy to help people with treatment-resistant depression and other conditions."

Let's learn more about 5-HT2A receptor

The 5-HT2A receptor is a G protein-coupled receptor that is a subtype of the 5-HT2 receptor and a member of the serotonin receptor family (GPCR). Despite having numerous internal sites, the 5-HT2A receptor is a cell surface receptor. Serotonin or 5-HT is also known as 5-hydroxy-tryptamine. For instance, if you eat a magic mushroom, the active ingredient pscilocin—which is derived from psilocybin—binds tightly to the 5-HT2A serotonin receptors on the surface of neurons.

Long-lasting activation of the receptor results in a cascade of chemical signals being sent inside of cells. These cells subsequently communicate with other brain cells, sending the individual on an extended, bizarre psychedelic experience for hours.

Psychedelic substances can instantly relieve depression in those who are treatment-resistant, and the relief lasts for several months.

Selective serotonin reuptake inhibitors (SSRIs), a family of antidepressants, influence serotonin transmission indirectly rather than directly, as psychedelic substances do.

"So, there's more going on than simply raising serotonin levels to treat depression," said Roth, who spent two decades seeing psychiatric patients.

"SSRIs cause changes in the brain that lead to anti-depressive action. We don't know what's going on exactly. But I know many people who have had their lives transformed by SSRIs and psychotherapy."

Overall, if the study makes a mark, the scientists will be created a compound that selectively hits the 5-HT2A receptor but activates it in a way that alters brain chemistry to treat depression, leaving the trippy pathway alone while avoiding the side effects associated with SSRIs.

Abstract:

There is considerable interest in screening ultra-large 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. 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 differs 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. 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.