CBD (yellow stick structure) interferes with binding of an opioid (green and red) by stabilizing an opioid receptor (gray) in its inactive form. Credit: Charles Kuntz
As the U.S. pushes for wider access to naloxone, a fast-acting opioid antidote, researchers are exploring cannabidiol (CBD) as a potential alternative due to its reduced effectiveness against synthetic opioids like fentanyl. A team has reported CBD-based compounds that decrease fentanyl binding and enhance naloxone’s effects. The findings will be presented at the ACS Spring 2023 hybrid meeting.
There’s been a recent push in the U.S. to make naloxone — a fast-acting opioid antidote — available without a prescription. This medication has saved lives, but it’s less effective against powerful synthetic opioids, such as fentanyl. In an interesting twist, researchers are now looking to cannabidiol (CBD), a component of marijuana, as a possible alternative to the popular antidote. Today, a team reports compounds based on CBD that reduce fentanyl binding and boost the effects of naloxone.
The researchers will present their results at the spring meeting of the American Chemical Society (ACS). ACS Spring 2023 is a hybrid meeting being held virtually and in-person March 26–30, and features more than 10,000 presentations on a wide range of science topics.
“Fentanyl-class compounds account for more than 80% of opioid overdose deaths, and these compounds aren’t going anywhere — it’s just too much of an economic temptation for dealers,” says Alex Straiker, Ph.D., the project’s co-principal investigator. “Given that naloxone is the only drug available to reverse overdoses, I think it makes sense to look at alternatives.”
A new option could take one of two forms, according to Michael VanNieuwenhze, Ph.D., the other co-principal investigator for the project.
“Ideally, we would like to discover a more potent replacement for naloxone,” VanNieuwenhze says. “However, finding something that works synergistically with it, reducing the amount needed to treat an overdose, would also be a success.”
Jessica Gudorf, a graduate student in VanNieuwenhze’s group, is presenting the work at the meeting. All of the researchers are at Indiana University Bloomington.
Opioids are a class of compounds that are prescribed to treat pain and are sometimes sold illegally. If taken in excess, the drugs can interfere with breathing, making them potentially lethal. The U.S. Centers for Disease Control and Prevention estimates that more than half a million people died from overdoses involving opioids between 1999 and 2020. That toll continues to climb.
Compared to other compounds in this class, such as heroin or morphine, fentanyl, and its other synthetic relatives bind more tightly to opioid receptors in the brain. Naloxone reverses an overdose by competing with the drug molecules for the same binding sites on the receptors. But because fentanyl binds so readily, it has a leg up on naloxone, and growing evidence suggests that reversing these kinds of overdoses may require multiple doses of the antidote.
At this point, researchers have exhaustively studied the strategy naloxone takes, but they have yet to find any way to improve on its performance, Gudorf says. “Our work opens the door to making new blockers that work through a different mechanism,” she explains.
Earlier research suggesting that CBD can interfere with opioid binding inspired the current effort. In research published in 2006, a group based in Germany concluded that CBD hampered opioid binding indirectly, by altering the shape of the receptor. When used with naloxone, they found CBD accelerated the medication’s effect, forcing the receptors to release opioids.
To augment these effects, Gudorf altered CBD’s structure to generate derivatives. Taryn Bosquez-Berger, a graduate student in Straiker’s group, tested these new compounds in cells with a substance called DAMGO, an opioid used only in lab studies. To measure their success, she monitored a molecular signal that diminishes when this type of drug binds. Armed with feedback from these experiments, Gudorf refined the structures she generated.
In the end, they narrowed the field to 15, which they tested at varying concentrations against fentanyl, with and without naloxone. Several derivatives could reduce fentanyl binding even at what Bosquez-Berger described as “incredibly low” concentrations, while also outperforming naloxone’s opioid-blocking performance. Two of these also showed a synergistic effect when combined with the antidote.
The team has since begun testing the most successful derivatives in mice. In these experiments, they are investigating whether these compounds alter behaviors associated with taking fentanyl.
“We hope our approach leads to the birth of new therapeutics, which, in the hands of emergency personnel, could save even more lives,” Bosquez-Berger says.
The researchers acknowledge support and funding from the Indiana University Grand Challenges Program.
Meeting: ACS Spring 2023
Title
Progress towards more efficacious medicine: Antibiotics and antidotes
Abstract
Development of innovative and efficacious medicine used for the treatment of health conditions and devastating diseases is at the forefront of pharmaceutical research as the results cannot only decrease overall drug cost, minimize adverse effects, and increase the therapeutic window, but also improve, prolong, and save lives. Globally, we are amidst severe health care crises related to bacterial resistance and opioid overdoses, which together claim millions of lives every year. Therefore, the development of more effective antibiotics and antidotes are necessary.
Antibiotic: One antibiotic that is underexplored is hypeptin, a non-ribosomal antibiotic that exhibits a broad range of activity against Gram-positive bacteria, including resistant strains, and is known to inhibit bacterial cell wall synthesis in a multifaceted approach. However, its exact mechanism(s) of action (MOA) is still unknown. To aid in elucidating its MOA, the design and progress towards the first total synthesis of hypeptin will be discussed along with activity-probing synthetic analogs.
Antidote: Naloxone, the only available antidote for opiate overdose, has a reduced therapeutic effect against fentanyl-class synthetic opioids as these potent agonists outcompete naloxone (antagonist) for the orthosteric site of the mu opioid receptor (µOR). Ergo, an alternative strategy to competitive antagonism is needed. Herein, investigations into the pharmacophore of hit compound (-)-cannabidiol (CBD) will be explored through structure activity relationship (SAR) studies with the goal of improving affinity and potency of this negative allosteric modulator (NAM). Through biological and computational efforts, fifteen of the fifty synthesized CBD analogs reversed µOR-mediated cyclic AMP inhibition induced by fentanyl, with several exhibiting much greater NAM potency than CBD. Additionally, the synergistic effects between naloxone and CBD analogs for the dissociation of fentanyl from the orthosteric site will be discussed.
Bravo.