Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models.
Nature communications – September 20, 2024
Source: PubMed
Summary
Imagine a single dose that could curb opioid cravings and reverse pain. New research suggests a modified natural compound might achieve this. Scientists developed "oxa-iboga" compounds, structurally edited to avoid the cardiac risks of related treatments. Tested in human heart cells and animal models, these compounds showed no heart side effects and remarkably suppressed opioid intake (morphine, heroin, fentanyl) and drug-seeking behavior. A single dose of oxa-noribogaine even reversed opioid-induced pain, offering long-lasting relief. This class of compounds presents a potent, safer path to treating opioid use disorder.
Abstract
Ibogaine and its main metabolite noribogaine provide important molecular prototypes for markedly different treatment of substance use disorders and co-morbid mental health illnesses. However, these compounds present a cardiac safety risk and a highly complex molecular mechanism. We introduce a class of iboga alkaloids - termed oxa-iboga - defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds lack the proarrhythmic adverse effects of ibogaine and noribogaine in primary human cardiomyocytes and show superior efficacy in animal models of opioid use disorder in male rats. They act as potent kappa opioid receptor agonists in vitro and in vivo, but exhibit atypical behavioral features compared to standard kappa opioid agonists. Oxa-noribogaine induces long-lasting suppression of morphine, heroin, and fentanyl intake after a single dose or a short treatment regimen, reversal of persistent opioid-induced hyperalgesia, and suppression of opioid drug seeking in rodent relapse models. As such, oxa-iboga compounds represent mechanistically distinct iboga analogs with therapeutic potential.