Nature A new hope for people with depression: powerful long-acting antidepressants

Scientists have discovered multiple pathways in which psychedelics activate the main receptors

Scientists have devised compounds capable of hitting the same key receptor activated by LSD without causing hallucinations
.
A single dose produced a powerful antidepressant and anxiolytic effect on mice for up to two weeks
.
The study, published September 28, 2022 in the journal Nature, may provide a way to develop novel antidepressants that are more effective and have fewer side effects than current drugs, which are ineffective for many patients and must be taken
daily.
It represents the pinnacle of six years of work for a team that began at the University of California, San Francisco, the University of North Carolina at Chapel Hill and Yale University, and later expanded to Duke and Stanford University
.

These compounds are designed to fit into the 5HT2a receptor, which is a prime target for psychedelics such as LSD and hallucinogenic mushrooms
.
This receptor is also activated by serotonin, a naturally occurring hormone that regulates mood, cognition, and many other functions
of the body.
The 5HT2a receptor is thought to play a role in schizophrenia and other psychotic disorders, as well as anxiety and depression, and many antipsychotics and antidepressants block its activity
.
New molecules activate it, but in a very different
way than psychedelics do.

Recent studies have found that when used in conjunction with psychotherapy, one to two doses of psychedelic agents, such as psilocybin and MDMA, can have significant long-term effects on
depression, anxiety and PTSD.
It's unclear whether the trip is essential for treatment or whether drugs
can be developed to relieve symptoms without traveling.
Current research offers the possibility
of unlocking these effects.
Although it has been known for decades that 5HT2a receptors activate different signaling pathways in cells, until now there have been no compounds that are selective enough to observe the effects of
each pathway.

The scientific team found that receptors can initiate two different pathways, one is the hallucinatory pathway and the other is the antidepressant/anxiolytic pathway
.
LSD activates the first one again, while the new compound activates the second
again.

"Receptors are like antennas," said
Dr.
Brian Shoichet, a professor of medicinal chemistry at UCSF's School of Pharmacy.
"They receive a chemical signal, and a bunch of things downstream are activated
in one cell.
"

Shoichet and other team members did not set out to find molecules
that could be used to make new drugs to treat depression.
Their initial goal was to find a way to screen for a molecule called tetrahydropyridine, which is difficult to synthesize and therefore not in a virtual library, although it is common
in FDA-approved drugs.

But another team member, Bryan Roth, MD, of the University of North Carolina at Chapel Hill, PhD, believes the molecules could be an interesting way to test the function of 5HT2b receptors, which he has been studying
with since the 1980s.

"Until psilocybin is used in clinical trials for depression and proven to have significant efficacy, there is no indication that drugs like psychedelics are able to activate this receptor and thus play a therapeutic role
," he said.
This really sparked our interest, which basically kicked off the collaboration
.
”

Roth, the Michael Hooker distinguished professor of pharmacology at the University of North Carolina School of Medicine, and a number of other team members recently addressed the crystal structure
of the 5HT2b receptor.
They used this structure to model 5HT2a until Ross's team came up with a crystal structure
for 5HT2a.

These compounds were selected from a computing pool of 75 million candidate compounds
.
They were
synthesized by Dr.
Jonathan Ellman, the Eugene Higgins Professor of Chemistry, and the Yale Professor of Pharmacology.
The UCSF, UNC, and Yale teams spent more than a year optimizing them
.

Shoichet said: "The final molecule is 100 times
stronger than the molecule we started with.
Although they are still not as strong
as LSD.
In animals, they are very effective, more effective
than Prozac.
”

The team scaled up, testing the design molecules on mice and complemented Dr.
William Wetsel, director of the Mouse Behavioral and Neuroendocrine Analysis Core Facility at Duke University.

His lab studied the head twitching responses of mice, which are signals
of psychedelic activity.
But the rats barely twitched
.

Wetsel's lab conducted a series of tests on mice to see if these molecules could improve symptoms
similar to anxiety and depression in humans.
They are very effective
.

Years later, this discovery, originally a scientific experiment, holds great promise
in the clinic.
The team's next project will optimize these compounds to be selective enough for use in clinical trials
.