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iNature
On November 10, 2022, the team of Xu Huaqiang, Xie Xin, and Wang Mingwei, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, cooperated in publishing a long article entitled "Molecular recognition of morphine and fentanyl by the human μ-opioid receptor" online in the top international journal Cell This study analyzes and reports the high-resolution three-dimensional structure of opioid analgesics such as fentanyl, morphine and olicuridine to activate μ opioid receptors (μOR), respectively, revealing for the first time the mechanism of
action by fentanyl and morphine to recognize and activate μOR 。 This study further combines a variety of cellular-level functional analysis and molecular dynamics simulation methods to clarify the structure-activity relationship between fentanyl series derivatives and the target μOR phase and the key structural basis of μOR-mediated inhibitor (Arrestin) signaling, systematically explore and deepen the understanding and understanding of the regulatory mechanism of μOR signal transduction, and point out the direction
for promoting the development of new opioid analgesics with high efficiency and low toxicity.
.
According to statistics, nearly 20% of adults worldwide suffer from chronic pain, and nearly 40%
in some economically backward countries.
Common chronic pains include low back pain, arthritis pain, migraine and cancer pain, which not only lead to weakening or loss of behavioral ability, but also bring about depression, sleep disorders and suicidal tendencies, seriously affecting people's physical and mental health, and causing huge social and economic burdens
.
Opioids are currently the most widely used and highly effective analgesics
.
Its application dates back thousands of years, to the plant poppy for analgesia, sedation and recreation (pleasure and euphoria).
Subsequent studies found that the opioid morphine was the main substance
that exerted activity in the poppy.
Common opioids include natural opioid alkaloids such as morphine and cocaine, and synthetic opioids such as demeraldine and fentanyl, which produce morphine-like effects
in the body.
Opioids act on opioid receptors in the G protein-coupled receptor family, especially μ μ-opioid receptors (μOR), mainly activating downstream inhibitory Gi/o proteins to exert pharmacological activities
such as analgesia.
The development of opioid receptor drugs has long been a research hotspot of analgesic drugs, and most of the opioids that have been marketed are agonists of μOR, and representative classic opioid analgesic drugs such as morphine and fentanyl have shown high selectivity
for μOR.
However, the use of opioid analgesics can lead to many toxic side effects, including addiction, respiratory depression and constipation, which greatly limits their clinical application and makes the development of safe and effective analgesic drugs targeting opioid receptors a major
difficulty.
Deaths from respiratory depression caused by opioid addiction have also directly contributed to the widespread "opioid crisis", mainly in North America, causing more than 100,000 deaths per year, mainly due to the abuse of fentanyl and its derivatives
.
However, as the main factor of the "opioid crisis" and a powerful analgesic drug still in clinical use, the molecular mechanism of fentanyl interaction with μOR has been unknown for a long time, which is of great
significance for the rational design of safer and more efficient fentanyl-derived analgesics.
Previous studies have shown that the analgesic effects of opioids are mediated by the μOR G protein signaling pathway, while the side effects are caused by the repressin signaling pathway
.
However, several recent studies have questioned this hypothesis, arguing that neurotoxic side effects such as respiratory depression are not
related to repressin signaling.
Despite the doubts, a large number of studies have been invested in the discovery of G protein-biased μOR agonists, aiming to develop high-efficiency and low-toxicity analgesic drugs targeting μOR
.
In 2020, the US FDA approved the first and currently the only μOR analgesic designed based on the concept of G protein bias, Oliceridine (TRV130), for the treatment of moderate to severe pain, which exhibits lower toxic side effects
than morphine.
Due to the lack of understanding of the G protein preference molecular mechanism of μOR, the discovery of G protein biased agonists of μOR has been obtained through large-scale high-throughput blind screening for nearly 20 years since the above hypothesis was proposed, which greatly hindered the rational design and discovery
of similar innovative analgesic drugs.
In this study, the researchers first analyzed the three-dimensional structures of human μOR binding to balanced agonists such as fentanyl, morphine and DAMGO (showing bidirectional signaling activity of G protein and repressin) and G protein-biased agonists such as TRV130, SR17018 and PZM21 by cryo-EM, and characterized
the transduction characteristics of agonist activated μOR of different signaling pathways through molecular dynamics simulation and cellular-level functional analysis 。 The study found that fentanyl occupies an additional binding pocket at the TM2 to TM3 proximal extracellular end of μOR compared to morphine, and in addition, fentanyl's aniline ring side chain forms a direct π-π hydrophobic interaction with amino acid residues W295 and Y328, which confers it with receptor-activating activity
up to 50-100 times higher than morphine.
Through molecular docking and point-mutation function verification of different fentanyl derivatives, the researchers further explored the structure-activity relationship of fentanyl and its derivatives, and found that different degrees of interaction between drug molecules and amino acid residues such as D149, Y150, W135 and W320 play a key role
in determining the different activities of fentanyl and its derivatives (carfentanil, sufentanil and oxymethamfentanil, etc.
).
。 The analysis of the analyzed series of structures and molecular dynamics simulations showed that the G protein biased agonist PZM21 was more inclined to bind to the TM2/3 side of the μOR ligand binding pocket, while the equilibrium agonist fentanyl showed a broader and more balanced interaction with the μOR transmembrane region, and made the intracellular domain of μOR more compact, which was conducive to the binding of μOR to repressin, thus explaining the molecular mechanism of equilibrium agonist manifestation of inhibitor activity
.
Based on these findings, the researchers also designed novel G protein-biased fentanyl derivatives FBD1 and FBD3
with different activities based on the fentanyl molecular backbone.
This study was completed by the team of Xu Huaqiang, Xie Xin and Wang Mingwei of Shanghai Institute of Materia Medica
.
Youwen Zhuang, associate researcher at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and Yue Wang, Bingqing He and Xinheng He, doctoral students, are co-first authors
of the paper.
Prof.
Huaqiang Xu, Prof.
Xin Xie, Prof.
Mingwei Wang (Department of Pharmacology, School of Basic Medical Sciences, Fudan University) and Associate Prof.
Youwen Zhuang are co-corresponding authors
.
Also participating in the study were Prof.
Xi Cheng, Prof.
Dehua Yang, Prof.
Yi Jiang, Prof.
Xiangrui Jiang, Dr.
Shimeng Guo, Prof.
Karsten Melcher of the Winanluo Institute, and Prof.
Karsten Melcher of the Winanluo Research Institute, and X.
Dr.
Edward Zhou et al
.
The research work was strongly supported
by Academician Jiang Hualiang and researcher Shen Jingshan of Shanghai Institute of Materia Medica.
Shanghai Yuansi Biotech provided compound samples
for this study.
The work was supported by the technical support of the cryo-EM platform and peak electron microscopy platform of the Shanghai Institute of Materia Medica, as well as the National Natural Science Foundation of China, the Key R&D Program of the Ministry of Science and Technology, the Pilot Project of the Chinese Academy of Sciences, the National Science and Technology Major Project (New Drug Creation Key Project), the Shanghai Science and Technology Major Project and the Special Assistant Research Project of the Chinese Academy of
Sciences.
Article link: https://doi.
org/10.
1016/j.
cell.
2022.
09.
041
expert commentator Zhang Xu (Academician of Chinese Academy of Sciences) According to the 2020 China Pain Medicine Development Report, nearly 10%-20% of the population in China is plagued by chronic pain including cancer pain, postoperative pain, nerve damage and muscle fiber pain, and the group of chronic pain patients has exceeded 300 million and is still growing
。 Pain has developed into the third major health problem in the current society after cancer and cardiovascular and cerebrovascular diseases, which has caused a huge impact and burden on people's lives and social and economic development, and the development of efficient and safe analgesics is a major demand
for current medical and health care.
Opioids are currently the most widely used and effective analgesic drugs.
The earliest human use of opioids was reflected in the discovery of the value of the plant opium poppy.
As an ancient medicinal plant, the poppy was mentioned as early as the Sumerian text around 4000 BC and was called Hul Gil (the delightful plant).
Opium is a class of alkaloid active substances extracted from the opium poppy, and its application in human history dates back thousands of years, mainly for pain relief treatment and recreational use.
The core active substance in opium is morphine, named after the Greek god of dreams, Morpheus, first isolated from opium in 1805 by the German pharmacist Friedrich Sertürner.
Morphine has a potent analgesic effect, but it is also accompanied by toxic side effects such as high addiction and respiratory depression.
In the pursuit of powerful, low-addiction analgesics, a series of opioids with different structures producing morphine-like physiological effects have been synthesized, including heroin discovered in 1874 and fentanyl synthesized in 1959.
Although these synthetic opioids exhibit stronger analgesic effects than natural opioid alkaloid morphine, they are also associated with more intense toxic side effects
.
The design and development of new opioid analgesics and even non-opioid analgesics that are highly effective in analgesia and avoid neurotoxic side effects has always been the unremitting pursuit
of scientists.
</b121<b122>> Opioids activate opioid receptors in the G protein-coupled receptor family to exert analgesic effects
by simulating the antinociceptive physiological effects of endogenous opioid peptides, such as endorphins and dynorphins.
Among them, morphine and fentanyl, as representatives of classical opioid analgesics, mainly play a role by activating μ opioid receptor (μ μOR), and are still used as clinical analgesics
.
For a long time, a large amount of research has focused on the scientific question of how the two can be combined with μOR, in order to design safer opioid analgesics based on structural information, especially after
the first μOR (inactive) structure was resolved in 2012.
However, the agonist binding model based on molecular docking and kinetic simulation of the inactivated structure is complex and cannot reflect the binding pattern
of the real agonist.
This study is the first to resolve a series of near-atomic-resolution structures of agonist morphine and fentanyl binding μOR, clarifies the understanding of the confusion of fentanyl binding patterns, gives us the first understanding of how it interacts with μOR, and provides a precise template
for the design of future painkillers.
The μOR-mediated arrestin signaling pathway is considered to be an important factor in the occurrence of opioid toxicity, which also led to the discovery of the G protein-biased ligand TRV130 and its approval
by the FDA in 2020 。 This study is also based on structural and multiple pharmacological function experiments and found that weakening the interaction of opioid molecules with the sixth and seventh transmembrane regions of μOR can weaken or even eliminate arrestin signaling, thereby triggering G protein biased signal transduction, which provides new ideas for subsequent design and discovery of opioids with pathway bias, which will promote the discovery
of highly effective and low-addictive analgesics.
the ——
