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 and Dalibor Sames ()
Additional contact information
Václav Havel: Columbia University
Andrew C. Kruegel: Columbia University
Benjamin Bechand: Columbia University
Scot McIntosh: High Point University
Leia Stallings: High Point University
Alana Hodges: High Point University
Madalee G. Wulf: Columbia University
Mel Nelson: Columbia University
Amanda Hunkele: Memorial Sloan Kettering Cancer Center
Michael Ansonoff: Rutgers University
John E. Pintar: Rutgers University
Christopher Hwu: Columbia University
Rohini S. Ople: University of Health Sciences & Pharmacy at St Louis and Washington University School of Medicine
Najah Abi-Gerges: Suite 200
Saheem A. Zaidi: University of Southern California
Vsevolod Katritch: University of Southern California
Mu Yang: Columbia University Irving Medical Center
Jonathan A. Javitch: Columbia University
Susruta Majumdar: Memorial Sloan Kettering Cancer Center
Scott E. Hemby: High Point University
Dalibor Sames: Columbia University

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51856-y

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