Fentanyl, a powerful opioid painkiller, is the leading cause of overdose death in the United States. In an effort to improve the drug’s safety profile to make it less lethal and addictive without eliminating its pain-relieving ability, a team of researchers, led by scientists from the Center for Clinical Pharmacology at Washington University School of Medicine in St. Louis and the St. Louis University of Health Sciences and Pharmacy changed the chemical properties of the drug and the way it binds to opioid receptors on nerve cells.
Their studies, conducted in mice and in cell lines expressing the opioid receptor, indicate that the modified drug is still an effective pain reliever, but probably doesn’t have as many life-threatening side effects. The research is published Nov. 30 in the journal Nature.
Although further studies are needed in other animal models and in humans to assess the modification strategy of fentanyl, the research shows promise for the development of safer opioid drugs that also provide pain relief.
“Opioids, including fentanyl, are some of the most effective painkillers we have, but they have also resulted in too many accidental deaths, a simply tragic situation,” said the paper’s corresponding author, Susruta Majumdar. , PhD, partner. professor of anesthesiology at the University of Washington and associate professor of medicinal chemistry and pharmacology at the University of Health Sciences and Pharmacy. “We are desperately looking for ways to maintain the pain-relieving effects of opioids, while avoiding the dangerous side effects such as addiction and respiratory distress that too often lead to death. Our research is still in its early stages, but we are excited about its potential to lead to safer pain medications.
Fentanyl is commonly used to manage severe pain in cancer patients and in patients undergoing major surgery. It is up to 50 times stronger than heroin and 100 times stronger than morphine, and synthetic fentanyls are often sold on the street mixed with other drugs, such as heroin and oxycodone. More than 150 people die every day in the United States from overdoses related to opioids like fentanyl.
Like heroin and oxycodone, fentanyl binds to the mu-opioid receptor on nerve cells. Once nested in the receptor, drugs such as fentanyl relieve pain, but can also lower blood pressure and slow breathing, which can lead to respiratory distress and even death. Other side effects include euphoria, dizziness, confusion, and sedation. Due to its potency, fentanyl is particularly deadly, even in very small amounts.
By modifying fentanyl, the researchers developed a variant of the drug that still binds to the mu-opioid receptor but also engages a sodium ion binding site present in the receptor. Majumdar said the research showed that by engaging the sodium binding site as a target, the pathway by which fentanyl works to combat pain was slightly altered, allowing the drug to maintain most of its pain-relieving effects while reducing adverse effects.
When the modified drug was tested in mice that had encountered a painful stimulus or in a mouse model of chronic pain, the drug retained its ability to relieve pain. Additionally, mice were less likely to experience respiratory depression than mice receiving the standard formulation of fentanyl, and behavioral studies in mice suggested lower abuse potential. Although the results are encouraging, Majumdar warned that more research is needed to understand the risks and potential benefits of modified fentanyl.
The mu-opioid receptor belongs to a family of cell receptors called G-protein-coupled receptors, which are able to bind hormones and signaling molecules, in addition to opioid drugs.
“The idea that sodium ion, something we find in table salt, might modulate the activity of G protein-coupled receptors, such as these opioid receptors, is not new, but our group seems to be the first to successfully modify the chemistry of fentanyl so that it interacts with the sodium site on the receptor,” Majumdar said.
And it turns out that many other drugs also target G-protein-coupled receptors, suggesting that these drugs could also be modified to reduce their side effects by modulating the sodium binding site present in these targets.
“Nearly a third of all drugs on the market today – from high blood pressure drugs to diabetes drugs to painkillers like fentanyl – bind to various G-protein-coupled receptors, so it can be possible to make many drugs more effective and limit their side effects, by changing the way they bind to these receptors,” he said.
Others involved in the new research include 2012 Nobel Laureate Brian Kobilka, MD, PhD, a professor of molecular and cellular physiology at Stanford Medicine, who trained as a medical resident at Barnes-Jewish Hospital and the Washington University School of Medicine in the early 1980s; Vsevolod Katritch, PhD, associate professor of quantitative and computational biology and chemistry at the University of Southern California; Georgios Skiniotis, PhD, professor of molecular and cellular physiology and structural biology at Stanford; and Jay P. McLaughlin, PhD, professor of pharmacodynamics at the University of Florida.
Most of the work was conducted at the Center for Clinical Pharmacology, a collaboration between the University of Washington and the University of Health Sciences and Pharmacy. Center researchers have academic appointments at both institutions. The center’s goal is to find better, safer and more effective ways to use prescription drugs to improve health. The initial objective was to better understand and improve the treatment of pain.
In future studies, the researchers plan to test their chemically modified fentanyl on other lab animals and make a form of the drug that will work systemically, like a pill, instead of the current injectable version.
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