The perfect painkiller that rivals morphine but is not addictive
August 22, 2016 Source: China Pharmaceutical Network
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];Recently, the journal Nature published an article that revealed an analgesic compound that is comparable to morphine. The most surprising thing is that it does not have obvious side effects such as respiratory depression, addiction, etc., at least in mouse experiments. This progress is very good news for doctors, patients and even the entire medical community.
This breakthrough was made by the scientific teams of Stanford University School of Medicine, the University of North Carolina (UNC) and the University of Erlangen-Nuremberg, where they assembled millions of drug screenings, medicinal chemistry analyses, and large-scale preclinical trials. A series of work, through outstanding results developed through interdisciplinary and inter-agency.
Currently, the drug has been proven to be unique in animals and does not make mice addicted. This progress is very good news for doctors, patients and even the entire medical community.
Start from scratch: find safer painkillers
Opioid analgesics can interact with the central nervous system to relieve pain. However, repeated use or excessive use is prone to side effects such as respiratory depression, drug dependence, and vomiting.
In recent decades, the number of deaths in the United States due to excessive use of opioids has been on the rise. In 2014, a total of 28,000 patients in the United States died of anesthesia, and more than half of them died of opioids. In February 2016, President Obama proposed investing $1.1 billion to treat opioid addiction. Last month, the US Congress passed a bill to curb the abuse of opioids and improve the status of treatment.
However, it is undeniable that even if the addiction is serious and the side effects are serious, opioids are still the most powerful weapon for modern medicine to fight against pain.
Therefore, scientists have been looking for compounds that can replace opioids.
Traditional drug development is based on the marketed drug (morphine), and its side effects are eliminated by changing its structure while preserving its original efficacy. But Brian Kobilka, a professor of molecular and cellular physiology at Stanford Medical School, and Brian Shoichet, a professor of medicinal chemistry at the University of California, San Francisco, didn't want to. They chose a more radical path: from the ground up, using computer algorithms to screen new compounds from drug libraries!
The key to problem solving: just analgesia, avoid side effects
In 2012, Aashish Manglik, a research team at Stanford University School of Medicine and other members of the Kobilka Laboratory, studied the three-dimensional structure of μ opioid receptors.
The μ opioid receptor is a member of the opioid receptor family and is structurally similar to proteins on the surface of brain and spinal cord cells. When morphine or other derivatives bind to the μ opioid receptor, the receptor releases a signal that activates the intracellular downstream pathway and ultimately achieves an analgesic effect.
It is worth noting that when morphine is combined with the μ opioid receptor, its analgesic effect is achieved by a series of special cascades in a signaling pathway. Their respiratory depression side effects are responsible for another signaling pathway.
After clearing these two signaling pathways, scientists tried to strip the pain relief effects and side effects. How to "take the essence to ruin" is the key to solving the problem. The idea of ​​the research team is to activate only the μ opioid receptor and avoid any other opioid receptors, thus only triggering the signaling pathway responsible for analgesic efficacy without touching the signaling pathways associated with side effects.
So, is there a small molecule with this perfect feature? Can the “one-stop pain-free journey†be achieved? Manglik has collaborated with a research team at the University of California, San Francisco.
From structure to computer: screening out perfect compounds
As co-author of the article, Dr. Henry Lin, a graduate student in the Pharmaceutical Chemistry Laboratory at the University of California, San Francisco, under the direction of his mentor, Professor Brian Shoichet, screened 3 million synthetic compounds in a "virtual pharmaceutical compound library" by computer algorithms.
As a result, they locked in 2,500 compounds that are predicted to bind to the μ opioid receptor. Subsequently, they narrowed the range again and eventually captured 23 compounds as candidates for further testing.
Lin and Shoichet are concerned that chemical structures are essentially different from those of marketed opioids, so that the signaling pathways that activate side effects are avoided. After taking this as a condition, the researchers finally found seven compounds.
From 1.0 to 3.0: The perfect transformation of new compounds
These compounds were sent to the laboratory of Dr. Bryan Roth, Professor of Pharmacology and Medicinal Chemistry. Roth conducted an in-depth analysis of them and eventually found that one of the compounds was able to strongly activate the "good" downstream pathway (analgesia) without involving the "bad" signal path (respiratory depression).
Although the advantages are significant, this compound (version 1.0) does not have enough power for treatment. To optimize its attributes, the Roth team worked with Professor Peter Gmeiner, head of FAU's pharmaceutical chemistry.
The Gmeiner team constructed multiple versions of the compound and determined that one of them (version 2.0) was better able to bind to the μ opioid receptor. Subsequently, Gmeiner added a hydroxyl group to the 2.0 version to make it more firmly conformable to the receptor binding site.
In the end, the 3.0 version of the molecule was born! The researchers named it "PZM21", which binds to the μ opioid receptor 1000 times stronger than the original version.
Not only does PZM21 not significantly activate other opioid receptors, but it also inhibits the activity of the Kappa receptor (which is associated with side effects such as anxiety and hallucinations).
The Roth team used mice as a model to confirm that PZM21 does have an analgesic effect and is comparable to morphine. Most importantly, the degree of respiratory depression in PZM21 is greatly reduced. At the same time, Stanford's research team constructed mutant mice without μ opioid receptors, and these mice did not show significant side effects after injection of PZM21.
Medical Cold Patch
Patch for diarrhea
[Name] Medical Cold Patch
[Package Dimension] 5cm 4pieces/box
The pain relief patch is composed of three layers, namely, backing lining, middle gel and protective film. It is free from pharmacological, immunological or metabolic ingredients.
[Scope of Application] For cold physiotherapy, closed soft tissue only.
[Indications]
The patches give a fast relief for diarrhea.
[How To Use a Patch]
Please follow the Schematic Diagram. One piece, one time.
The curing effect of each piece can last for 6-8 hours.
[Attention]
Do not apply the patch on the problematic skin, such as wounds, eczema, dermatitis,or in the eyes. People allergic to herbs and the pregnant are advised not to use the medication. If swelling or irritation occurs, please stop using and if any of these effects persist or worsen.notify your doctor or pharmacist promptly. Children using the patch must be supervised by adults.
[Storage Conditions]
Store below 30c in a dry place away from heat and direct sunlight.
Patch For Diarrhea,Medicated Patches For Arthiritis,Plaster For Diarrhea,Pad For Diarrhea
Shandong XiJieYiTong International Trade Co.,Ltd. , https://www.xijieyitongpatches.com