Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models

Authors
Havel, Vaclav, Kruegel, Andrew C., Bechand, Benjamin, McIntosh, Scot, Stallings, Leia, Hodges, Alana, Wulf, Madalee G., Nelson, Mel, Hunkele, Amanda, Ansonoff, Michael, Pintar, John E., Hwu, Christopher, Ople, Rohini S., Abi-Gerges, Najah, Zaidi, Saheem A., Katritch, Vsevolod, Yang, Mu, Javitch, Jonathan A., Majumdar, Susruta, Hemby, Scott E., Sames, Dalibor


Lab

Journal
Nature Communications

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. Ibogaine is a natural substance that interrupts opioid addiction but has cardiac risks. This article introduces novel ibogaine analogs that show reduced cardiac risk and enhanced neuroplasticity and therapeutic-like effects in models of opioid use disorder.

Keywords/Topics
oxa-iboga;alkaloids;cardiac;disrupt;opioid;animal;models;ibogaine;metabolite;noribogaine

BIOSEB Instruments Used:
Electronic Von Frey 5 with embedded camera (BIO-EVF5),Modular holder cages for rats and mice (BIO-PVF)

Source :

https://www.nature.com/articles/s41467-024-51856-y

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