Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models.
Václav Havel, Andrew C Kruegel, Benjamin Bechand, Scot Mcintosh, Leia Stallings, Alana Hodges, Madalee G Wulf, Mel Nelson, Amanda Hunkele, Michael Ansonoff, John E Pintar, Christopher Hwu, Rohini S Ople, Najah Abi-Gerges, Saheem A Zaidi, Vsevolod Katritch, Mu Yang, Jonathan A Javitch, Susruta Majumdar, Scott E Hemby, Dalibor Sames
Nature communications September 20, 2024 DOI: 10.1038/s41467-024-51856-y via PubMed
Summary
AI-generated from the abstractA new class of iboga alkaloids, called oxa-iboga, was created by modifying the iboga molecular structure to replace a key component with a benzofuran ring. These compounds lack the heart rhythm risks (proarrhythmic effects) of ibogaine and noribogaine when tested on human heart cells. In male rats, oxa-iboga compounds were more effective than ibogaine at reducing opioid use. They act as potent kappa opioid receptor agonists but produce different behavioral effects than typical kappa agonists. A single dose or short treatment with oxa-noribogaine led to long-lasting reductions in morphine, heroin, and fentanyl intake, reversed persistent opioid-induced pain sensitivity, and suppressed drug-seeking behavior in relapse models. These compounds offer a mechanistically distinct approach to treating opioid use disorder.
Study at a glance
| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Male rats and primary human cardiomyocytes |
| Interventions | oxa-iboga compounds oxa-noribogaine |
| Dose | a single dose or a short treatment regimen |
| Keywords | Drug discovery Pain management Drug safety |
| Citations | 18 |
| Key finding | Oxa-iboga compounds lack proarrhythmic cardiac effects and show superior efficacy in reducing opioid intake and relapse in animal models, acting as atypical kappa opioid receptor agonists. |
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.