Researchers have discovered a potential new way to reverse fentanyl overdose by using modified cannabidiol (CBD) as a negative allosteric modulator of opioid receptor binding sites. Initial in vitro studies showed that modified CBD was successful in reversing the effects of fentanyl, and further in vivo studies are underway to assess its ability to counter respiratory depression, the primary overdose effect. is planned.
According to the Centers for Disease Control and Prevention, overdoses claim the lives of 100,000 Americans each year, the vast majority of which are due to ingestion of synthetic opiates. Fentanyl. Naloxone, now the only antidote for opiate overdoses, is becoming more widely available but is less effective against synthetic opioids in the fentanyl class.
Researchers at Indiana University have identified a new way to reverse the effects of fentanyl, which is 50 to 100 times more potent than morphine. Their research is Medicinal Chemistry Journalnew products, or working in sync with naloxone could lead to new ways to reverse overdoses.
“Synthetic opiates bind very tightly to opioid receptors,” says Alex Stryker, a senior research scientist at the Gill Center for Biomolecular Sciences. “To counteract an overdose, naloxone has to compete with the opioid for the same binding site in the central nervous system. However, in a fentanyl overdose, naloxone and fentanyl bind to different sites, so there is no competition. We wanted to know whether negative allosteric modulators could reverse the effects of fentanyl.”
Striker began measuring the effects of opioid receptors on a signaling molecule called cAMP. To identify which compounds are most promising as effective negative allosteric modulators, 50 structurally related molecules were chemically tested.
researchers discovered cannabidiol, or CBD may act as a negative allosteric modulator at the binding site. However, initial tests required high concentrations. Researchers modified the structure of cannabidiol to make it more effective and found they were able to reverse the effects of fentanyl in in vitro (tests performed on blood or tissue samples) diagnostics.
“We have identified structural parts that are important for the desired detoxification effects,” Straker said. “Some of these compounds are much more powerful than lead. We are working with a third lab to identify binding sites that may help identify additional compounds in the future. I modeled it.”
The next step is to test the findings in vivo, or in living organisms, to determine whether it reverses the main overdose effect, respiratory depression.
Reference: “Structure-activity relationship studies of cannabidiol-based analogs as negative allosteric modulators of μ-opioid receptors” Taryn Bosquez-Berger, Jessica A. Gudorf, Charles P. Kuntz, Jacob A. Desmond, Jonathan P. Schlebach, Michael S. VanNieuwenhze and Alex Stryker, July 12, 2023. Medicinal Chemistry Journal.
DOI: 10.1021/acs.jmedchem.3c00061
Additional authors on the study are Taryn Bosquez-Berger, IU Bloomington, Ph.D. in Psychology and Brain Sciences; The candidates are IU Bloomington organic chemistry graduate student Jessica A. Gudorf, IU Bloomington chemistry assistant professors Charles P. Kunz and Jonathan P. Schulbach, and IU Bloomington chemistry professor Standiford H. Cox. My name is Michael S. Van Nieuwenze.
