In the present study, the researchers used a computational approach to identify compounds that may have therapeutic effects similar to psychedelic drugs.

Conventional approaches to drug discovery use high-throughput assays that allow researchers to screen a few million compounds simultaneously to identify candidates that may have the desired biological activity. However, this approach can be time-consuming and costly.

Moreover, due to a focus on efficiency, conventional approaches have generally focused on compounds synthesized using a small number of well-characterized reactions and readily-available building blocks. As a result, the number of molecules available for screening using the conventional approach is relatively small in comparison with the larger pool of compounds that could be potentially synthesized.

Researchers have used computational methods to construct virtual libraries and identify drug candidates to address these shortcomings. These virtual libraries contain not only compounds that have already been synthesized but also several millions of virtual compounds that could be synthesized.

Computational methods can simulate how the virtual library compounds interact with the biological target and identify drug candidates. This virtual screening process involves computing the docking scores, which estimate the strength of the interaction between the small molecule and the target protein.

Calculating the docking score is challenging due to the complex nature of chemical interactions between the three-dimensional structure of the target protein and the small molecule candidate. Furthermore, the candidate molecules are often flexible and can assume multiple conformations.

As a result, after a few candidate compounds are chemically synthesized, they require testing and optimization.

Nearly one-third of individuals with depression do not respond to current treatments, and there is a need for safe and effective drugs for treatment-resistant depression.

Emerging evidence suggests that psychedelic drugs are a promising therapeutic option for hard-to-treat depression.

The antidepressant and anti-anxiety effects of psychedelic drugs such as lysergic acid diethylamide (LSD) and psilocybin have been attributed to their ability to activate the serotonin 5-HT2A receptors on the surface of brain cells.

However, psychedelic drugs can produce hallucinogenic side effects by activating the 5-HT2A receptor.

The activation of the 5-HT2A receptor can activate two different signaling pathways inside the cells, which involve the β-arrestin-2 and the G_q protein.

Previous studies have shown that the hallucinogenic effects of LSD are mediated to a large extent by the signaling pathway involving the β-arrestin-2 protein. Thus, it is possible that compounds that activate the 5-HT2A receptor without activating the β-arrestin-2 pathway could help treat depression without causing unwanted hallucinogenic adverse effects.

Such compounds could offer numerous advantages over psychedelic drugs in treating depression and other psychiatric disorders. Dr. David A. Merrill, Ph.D., psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center at Providence Saint John’s Health Center in Santa Monica, said:

“Non-psychedelic anti-depressants also do not require the intensive staffing, space, and safety requirements necessary for classic psychedelics. It’s easy to imagine that non-hallucinogenic psychedelic-like substances that retain their anti-depressant and anti-anxiety properties but do not have psychedelic properties could be given to patients to take home and self-administer or even be delivered to patient’s homes without needing to travel in for the prolonged office-based sessions used with current psychedelic therapies.”

In the current study, the researchers were interested in compounds sharing a molecular motif or scaffold called tetrahydropyridine (TPH).

The THP motif is found in several drugs, including LSD and the anticancer medications vinblastine and vincristine. The chemical structure of THP makes molecules containing this motif well-suited to bind to the 5-HT2A receptor.

Although current virtual libraries include many molecules, certain compounds, such as those containing the tetrahydropyridine motif, are underrepresented in these libraries. The underrepresentation of tetrahydropyridines is due to the challenges associated with synthesizing derivatives containing this structural motif.

In their previous work, the study’s authors had come up with novel chemical reactions for synthesizing THP derivatives using commercially available building blocks. Building on their previous work, the researchers created a virtual library consisting of 75 million low molecular weight THP derivatives.

The researchers first screened the virtual library for THP derivatives that could bind a model of the 5-HT2A receptor. They initially synthesized 17 candidates with high docking scores and tested the ability of these compounds to activate the 5-HT2A receptor in laboratory cultured cells.

After testing these compounds, the researchers found four molecules that weakly activated the 5-HT2A receptor. With the aid of computational methods and additional testing, they optimized the design of these compounds to derive two compounds that could strongly bind the 5-HT2A receptor.

In subsequent experiments, the researchers examined the behavioral effects of these compounds in mouse models. Psychedelic drugs like LSD produce hallucinogenic symptoms such as head twitches and increased locomotor activity in mice.

Unlike LSD, the two novel compounds produced low levels of head twitches and did not result in excessive locomotion. These compounds also did not have rewarding properties commonly associated with drugs of abuse.

Significantly, these novel compounds produced antidepressant and anti-anxiety effects in mouse models.

These compounds reduced depression-like symptoms at 20-fold lower doses than the antidepressant fluoxetine (Prozac). In addition, the effects of these compounds on depressive symptoms were long lasting, with a single dose producing antidepressant effects lasting 14 days.

Jianjun Cheng, Ph.D., a professor at ShanghaiTech University specializing in medicinal chemistry, not involved in the study, told MNT:

“This study is an excellent example of how a combination of new chemistry and ultra-large screening leads to novel biologically active molecules. The game-changing trend of psychedelics as novel therapeutics for mental disorders such as depression and anxiety is getting extensive attention.”

“More new chemical entities (NCEs) with the same overall 5-HT2A agonist activity but distinct transduction efficiency, signaling bias properties, and selectivity profiles will be critical for determining the optimal pharmacological profile of 5-HT2A agonists as therapeutic drugs,” Prof. Cheng added.

“Advancing non-hallucinogenic 5-HT2A agonists into clinical tests is very important, which could provide safer alternatives to the psychedelics currently in clinical trials.”