Professor Yang Du of Science and collaborators published the development of non-opioid addiction-free analgesic drugs

The pain and opioid abuse pandemic has highlighted the need for new non-opioid treatments for
pain.
Many non-opioid receptors are involved in pain management (injury perception), but only a few of them are analgesic targets that have been proven
therapeutically.
α 2A-adrenergic receptor (α_2AAR) is a class A G-protein coupled receptor (GPCR) whose activation in the central nervous system has a pain-relieving effect
.
Drugs known to act on α_2AAR, such as the imidazole clonidine (clonidine) and dexmedetomidine (dexmedetomidine), have an analgesic effect
.
Unfortunately, they also have a strong calming effect; This sedative effect is important for the main indications of these drugs, but limits their widespread use
as analgesics in hospitals.
Since α_2AAR can bind to a variety of downstream signaling proteins (such as G protein, inhibitory protein arrestin, etc.
), resulting in different physiological effects (such as analgesia, sedative), the development of a structure different from clonidine, dexmedetomidine and other traditional imidazole drugs, and can selectively (bias) activate downstream specific signaling pathways of the new agonist, may eliminate or reduce its sedative effect, thus
。

Professor Du Yang of the Faculty of Medicine of the Chinese University of Hong Kong (Shenzhen) / Kobilka Institute for Innovative Drug Development, together with the team of Professor Peter Gmeiner of the University of Erlangen-Nuremberg and Professor Brian Shoichet of the University of California, San Francisco, jointly published the latest research results in the journal Science: Structure-based discovery of nonopioid analgesics acting through the α_2A-adrenergic receptor
。

The study screened 17 ligands α_2AAR from 301 million virtual molecules through molecular docking with affinity as low as 12 nM, many of which are partial agonists and biased toward the G_i and G_O signaling pathways
.
The researchers analyzed the structure of two ligands, α_2AAR complex, through single-molecule cryo-electron microscopy, confirmed the prediction of molecular butt, and used this as a template to further optimize the ligand structure
.
'9087 (initially screened agonist, median effective concentration (EC 50) 52 nM) and its two analogues, '7075 and PS75 (EC₅₀ 4.
1 and 4.
8 nM, respectively), exhibit analgesic effects in several in vivo pain models without sedative effects and off-target effects
.
These newly discovered agonists show rich drug-making potential and demonstrate advantages
in the absence of drug dependence (compared to opioids) and sedative effects (compared to imidazoles dexmedetomidine, etc.
).

The work reveals three important findings
.
First, effective agonists can be screened directly from large databases and can be independent
of known agonists.
Molecular docking can identify molecules with in vitro activity and make them active in vivo through structural activity
optimization.
Although direct detection of effective agonists is rare, the direct hit of effective ligands in this experiment does demonstrate the advantages of large virtual screening libraries, especially the efficacy
of chemical forms different from known ligands.
Second, although '9087 and its analogues '7075 and PS75 bias to the Gi/o/z pathway did not β repressor path activity, they were not designed with functional selectivity as the design criterion, possibly because of their new chemical form
.
Although similar situations often occur in other studies, the logic that uncharacterized chemical forms cause new signaling pathways needs more study
.
Third, '9087 and its analogues '7075 and PS75 do not cause sedation or movement impairment at analgesic doses, which has a wide range of applications and proves that α_2AAR agonists can be distinguished
according to two effects.

The study screened out some agonists with low EC₅₀ α_2AAR from a very large database and were not related to known ligands, allowing previously undiscovered ligand receptor interactions to confer new pharmacology
.
Some previously uncharacterized agonists play an abnormal and analgesic role in neurological and inflammatory pain models and can relieve acute nociception
in normal animals.
The most promising are '9087 and PS75, both of which have a strong analgesic effect, do not have the sedative side effects of dexmedetomidine, and are oral
.
Although their cardiovascular side effects have not been adequately studied, these drug precursors bring new light
to new non-opioid pain therapies.

Jun, a postdoctoral fellow at Stanford University School of Medicine/former research assistant at Kobilka Institute, Elissa Fink, a doctoral student at the University of California, San Francisco, and Harald Hubner, a Ph.
D.
at the University of Erlangen-Nuremberg, are tied as the first authors
.

Professor Du Yang: National high-level talent, principal and scholar, outstanding teacher in
Shenzhen.
Research Fellow, School of Medicine, Chinese University, Hong Kong, Shenzhen/Kobilka Institute for
Innovative Drug Development.
After obtaining his Ph.
D.
from the University of Science and Technology of China, he went to the Stanford University School of Medicine in the United States to work as a postdoctoral and research scientist for many years under Professor Brian Kobilka, the winner of the 2012 Nobel Prize in Chemistry, and won a full scholarship from the American Heart Association and a tenure-track assistant professor at the Ann Arbor School of Medicine at the University of Michigan
.

In 2019, Professor Du returned to China to join the University of Chinese of Hong Kong (Shenzhen) to participate in the establishment of the Kobilka Institute for Innovative Drug Development
.
Over the past three years, more than a dozen cutting-edge biomedical work
has been published by corresponding authors (including co-authors) in Cell, Science, Cell Research, Nature Comm.
, Science Advances, and more.
It has been selected into the high-level talent program at all levels such as national provinces and municipalities, and undertakes a number of scientific research projects at all levels to carry out research
.
At present, the laboratory has sufficient scientific research funds, and sincerely recruits colleagues who are interested in basic and translational research work such as important drug target structure research, antibody development and new drug discovery, and actively applies for postdoctoral and doctoral / master students
.

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