Drugs targeting receptors of the neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) are widely used in neuropsychiatry and some such agents, most notably psilocybin, have shown potential for further drug development, but hallucinogenic effects have limited their clinical use.

The findings of a new multicenter Chinese structural pharmacology study may now provide a solid basis for the structure-based design of safe and nonhallucinogenic psychedelic analogues with therapeutic efficacy, the authors reported in the January 28, 2022, edition of Science.

In this regard, the hallucinogens D-lysergic acid diethylamide (LSD) and psilocybin have shown particular promise in neuropsychiatric diseases. Small trials have shown their potential in mood disorders and anxiety.

In particular, recent studies have shown that psilocybin and LSD both appear to have rapid and enduring therapeutic effects and may represent viable alternatives to currently used antidepressants, which have clinical limitations.

"Conventional antidepressants have therapeutic effects only after several weeks of daily dosing and even then may not alleviate all the symptoms of the disease," lead researcher Sheng Wang told BioWorld Science.

Moreover, "approximately 30% of depression patients fail to respond to current antidepressant treatments," said the professor in the Center for Excellence in Molecular Cell Science at the University of the Chinese Academy of Sciences in Shanghai.

In contrast, "a phase II clinical trial has recently shown that psilocybin can significantly improve the symptoms of patients with depression within 1 day of dosing, and that the effect can last for even more than 3 months," Wang said.

Interestingly, in sleep-deprived animals, the endogenous fatty acid, oleamide, has been demonstrated to potentiate human 5-HT2A receptor (5-HT2AR)-mediated signaling.

Such observations suggest that abnormal sensitivity of 5-HT2AR to oleamide could underlie certain aspects of psychiatric disorders, including anxiety and depression.

However, a lack of structural information of 5-HT2AR in conjugation with fatty acids has limited structural-based design of safe and effective antidepressants.

Moreover, despite two recent reports of nonhallucinogenic analogues with antidepressant-like behavior, how to rationally design such compounds and whether their hallucinogenic effects are necessary for therapeutic effects remains unclear.

In their new Science study, Wang and Jianjun Cheng, a professor in the iHuman Institute at ShanghaiTech University in Shanghai, used X-ray crystallography to elucidate the structures of 5-HT2AR in complex with psilocin, the active metabolite of psilocybin, LSD, and serotonin and the nonhallucinogenic psychedelic analogue lisuride.

"Lisuride is an analogue of LSD without hallucinogenic effects in humans," explained Wang. "Through comparing LSD-bound and lisuride-bound 5-HT2AR structures, we were able to identify the key residue responsible for hallucinations."

In addition to their primary binding, serotonin and psilocybin were shown to display a secondary binding mode, which enabled the researchers to design the new chemotype psychedelic IHCH-7113, a substructure of the antipsychotic lumateperone (Caplyta; Bristol Myers Squibb Co.).

"We found that psilocin displayed a second binding mode, known as the extended binding pocket (EBP), which is regulated by lipids," Wang said.

"Compounds preferentially occupying more EBPs than the classical orthosteric binding pockets (OBPs) were [shown to be] associated with antidepressive activity in mice, without triggering hallucinations."

These findings enabled the researchers to design several biased agonists displaying antidepressant-like activity in mice, but without hallucinogenic effects.

"Members of the G protein-coupled receptor (GPCR) superfamily represent some of the most successful targets of modern drug therapy, with proven efficacy in a broad range of human conditions and disease processes," noted Wang. "The binding of an agonist to a GPCR promotes a conformational change resulting in the activation of receptor-associated heterotrimeric G proteins and consequent downstream signaling," he said.

"In addition to G protein activation, the binding also causes an aggregation of proteins called beta-arrestins that modulate the activity of the GPCRs.

"5-HT2AR beta-arrestin-biased agonists responding more to activating beta-arrestin-mediated than G protein-mediated activity were associated with antidepressive activity in the mice without triggering hallucinations," said Wang.

However, despite the beta-arrestin activity of the 5-HT2AR agonists being found to play a key role in their antidepressant effects, this is insufficient for inducing psychoactive actions.

Indeed, previous studies in humans have reported that a 50-70% 5-HT2AR occupancy level is required for an intense psilocybin-induced psychological experience.

Given recent successes in leveraging crystal structures of GPCRs for ligand discovery, including opioid, dopamine and melatonin receptors, structures reported here should speed the search for new psychedelics and nonhallucinogenic analogues for treating neuropsychiatric diseases.

In the meantime, said Wang, "we will be continuing to optimize our initial rapid-acting nonhallucinogenic antidepressant compounds and hopefully verify their safety and antidepressant effects in humans in the near future."