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WashU, pharmacy scientists alter fentanyl, aim to make it less lethal, less addictive

Goal is to reduce dangerous side effects of potent opioid pain reliever

by Jim DrydenNovember 30, 2022

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Fentanyl, a powerful opioid pain reliever, is the leading cause of overdose deaths in the United States. With the aim of improving the drug’s safety profile to make it less lethal and addictive without eliminating its ability to alleviate pain, a team of researchers, led by scientists at the Center for Clinical Pharmacology at Washington University School of Medicine in St. Louis and the University of Health Sciences & Pharmacy in St. Louis, have altered the drug’s chemical properties and the way that 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 still is an effective pain reliever but likely doesn’t have as many potentially deadly side effects. The research is published Nov. 30 in the journal Nature.

Although more studies are needed in additional animal models and in people to evaluate the strategy of modifying fentanyl, the research holds promise for developing safer opioid drugs that also relieve pain.

“Opioids, including fentanyl, are among the most effective pain-relieving drugs we have, but they also have led to too many accidental deaths, a situation that is simply tragic,” said the paper’s corresponding author, Susruta Majumdar, PhD, an associate professor of anesthesiology at Washington University and an associate professor of medicinal chemistry & pharmacology at the University of Health Sciences & Pharmacy. “We are desperately looking for ways to maintain the analgesic effects of opioids, while avoiding 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’re excited about its potential for leading to safer pain-relieving drugs.”

Fentanyl commonly is 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 designer fentanyls often are sold on the street mixed with other drugs, such as heroin and oxycodone. More than 150 people die in the U.S. every day of overdoses related to opioid drugs such as fentanyl.

Like heroin and oxycodone, fentanyl binds to the mu-opioid receptor on nerve cells. Once nestled into the receptor, drugs such as fentanyl relieve pain but also can lower blood pressure and slow breathing, potentially leading to respiratory distress and even death. Other side effects include euphoria, dizziness, confusion and sedation. Because of its potency, fentanyl is especially lethal, even in very small amounts.

In altering fentanyl, the researchers developed a variation of the drug that still binds to the mu-opioid receptor but that 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 through which fentanyl acts to combat pain was slightly altered, making it possible for the drug to maintain most of its analgesic effects while also reducing the adverse effects.

When the altered 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. In addition, the mice were less likely to experience respiratory depression than mice given the standard formulation of fentanyl, and behavioral studies in the mice suggested lower abuse potential. While the findings are encouraging, Majumdar cautioned that more research is needed to understand the potential risks and benefits of the modified fentanyl.

The mu-opioid receptor belongs to a family of cellular receptors called G-protein coupled receptors, which are able to bind hormones and signaling molecules, in addition to opioid drugs.

“The idea that the sodium ion, something we find in table salt, could modulate the activity of G-protein coupled receptors, such as these opioid receptors, is not new, but our group appears to be the first to successfully alter the chemistry of fentanyl so that it interacts with the sodium site on the receptor,” Majumdar said.

And it turns out many other drugs also target G-protein coupled receptors, which suggests that such drugs also could be modified to reduce their side effects by modulating the sodium binding site present in these targets.

“Almost one-third of all drugs currently on the market — from blood pressure drugs to diabetes drugs to analgesics like fentanyl — bind to various G-protein coupled receptors, so it may be possible to make many drugs more effective, and to limit their side effects, by altering how they bind with such 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 Washington University School of Medicine in the early 1980s; Vsevolod Katritch, PhD, an associate professor of quantitative & computational biology and of chemistry at the University of Southern California; Georgios Skiniotis, PhD, a professor of molecular & cellular physiology and of 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 Washington University and the University of Health Sciences & Pharmacy. The center’s researchers have academic appointments at both institutions. The center’s focus is on finding better, safer and more effective ways to use prescription medications to improve health. The initial focus has been to better understand and improve pain treatment.

In future studies, the researchers plan to test their chemically altered fentanyl in other laboratory animals and to make a form of the drug that will work systemically, like a pill, in place of the current injectable version.

Faouzi A, et al. Structure-based design of bitopic ligands for the m-opioid receptor. Nature, Nov. 30, 2022.

This work is supported by the National Institute of Drug Abuse and the National Cancer Institute of the National Institutes of Health (NIH). Grant numbers include R33 DA045884, R01 DA042888, R01 DA007242, R37 DA036246, R33DA 038858, P01 DA035764, R21 DA048650, R00 DA038725 and P30 CA008748. Additional funding provided by an American Heart Association Postdoctoral Fellowship, the Mathers Foundation, the Brain & Behavior Research Foundation and other funders (see the paper for the entire list).

About Washington University School of Medicine

WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,700 faculty. Its National Institutes of Health (NIH) research funding portfolio is the fourth largest among U.S. medical schools, has grown 54% in the last five years, and, together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,790 faculty physicians practicing at over 60 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children’s hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.

Jim retired from Washington University in 2023. While at WashU, Jim covered psychiatry and neuroscience, pain and opioid research, orthopedics, diabetes, obesity, nutrition and aging. He formerly worked at KWMU (now St. Louis Public Radio) as a reporter and anchor, and his stories from the Midwest also were broadcast on NPR. Jim hosted the School of Medicine's Show Me the Science podcast, which highlights the outstanding research, education and clinical care underway at the School of Medicine. He has a bachelor's degree in English literature from the University of Missouri-St. Louis.