Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models.
Václav Havel, Andrew C Kruegel, Benjamin Bechand, Scot Mcintosh, Leia S. 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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| 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 |
| Topics | Ibogaine |
| Keywords | Drug discovery Pain management Drug safety |
| Citations | 18 |
| Key points | 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.