Antidepressants are designed to target the LSD psychedelic receptor 5HT2a without causing hallucinations

LSD - diacetamide kerate, the strongest psychedelic drug, has a strong tendency to abuse, colorless, odorless, tasteless and imperceptible, potent and strong, microgram levels have reached an effective dose, even if taken once will also produce anxiety, panic and obvious mental disorders, LSD caused mental illness similar to some schizophrenia
.
The 5HT_2A receptor is a major target for psychedelics such as LSD
.
This receptor is also activated
by serotonin.
5HT_2A receptors are thought to play a role
in schizophrenia and other mental disorders, as well as anxiety and depression.
Many antipsychotics and antidepressants block its activity
.
According to an article in the journal Nature ("5-HT2A Receptor Agonists Dock with a Customized Library of Antidepressant Activity"), researchers from the University of California, San Francisco, Unc Chapel Hill, and Yale, Duke and Stanford have successfully devised compounds that target key receptors activated by LSD without hallucinating
。 The antidepressant and anxiolytic effects produced by a single dose on mice can last for two weeks
.
Given that existing antidepressants are currently ineffective for many patients and must be taken daily, this research may provide a pathway
to developing new antidepressants that are more effective and have fewer side effects than existing ones.

Filtering through the vast library of virtualization materials used to discover ligands is now a popular method
.
The researchers explored a customized virtual library of tetrahydropyridine suitable for many aminoenergetic G protein-coupled receptors using three inputs that docked a virtual library containing 75 million tetrahydropyridine with a 5HT_2A receptor model to synthesize and test 17 initial molecules
.
Four of these molecules have low molar activity
against 5-HT_2A or 5-HT_2B receptors.
Structure-based optimization obtained 5-HT2AR agonists (R) -69 and (R)-70 with semi-maximum effective concentration values of 41 nM and 110 nM, respectively, and unusual signal dynamics different from psychedelic 5-HT2AR agonists
.
Cryo-electron microscopy structural analysis confirmed the predicted binding pattern with 5-HT2AR
.
The good physical properties of these new agonists give high brain permeability, enabling behavioral analysis in mice
.

"It is worth noting that neither drug has psychedelic activity compared to the classic 5-HT2AR agonist, and in the mouse model, both have strong antidepressant activity and have the same efficacy
as antidepressants such as fluoxetine (fluoxetine) at doses as low as 1/40 of the dose of fluoxetine (fluoxetine).
" We will consider sampling
pharmacology-related chemical spaces using a custom virtual library.
”

These compounds are designed to fit into 5HT2a receptors, which are the primary targets
of psychedelics such as LSD and psilocybin 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 psychiatric disorders, as well as anxiety and depression, and many antipsychotic and antidepressant drugs block its activity
.
New molecules activate it, but in a different
way than hallucinogens.

Recent studies have found that when used in conjunction with psychotherapy, one to two doses of large doses of psychedelic drugs, such as psilocybin and ecstasy, can have significant long-term effects on
depression, anxiety and PTSD.
It is unclear whether such travel is essential for treatment, or whether drugs
can be developed that relieve symptoms without such travel.

Current research offers the possibility
of unlocking these effects.
Although it was known for decades that 5HT2a receptors activate different signaling pathways in cells, until now, no compound had been selective enough to observe the effects of
each pathway.

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

Dr.
Brian Shoichet, a professor of medicinal chemistry at the UCSF School of Pharmacy, said: "Receptors are like antennas
.
" "They receive a chemical signal, and then a series of substances in downstream cells are activated
.
The final molecule is 100 times stronger than the molecule we started with, "although far less powerful
than LSD.
" He added: "In animals, they are effective, much more
effective than Prozac.
"

The team's next project will be to optimize compounds so that they are selective enough for clinical trials
.
The method has been patented by Yale University, the University of North Carolina at Chapel Hill and the University of California, San Francisco, and licensed to Canadian startup Onsero
.