Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models
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.
Authors
- Christopher Hwu (ORCID: https://orcid.org/0000-0001-7320-036X)
- Dalibor Sameš (ORCID: https://orcid.org/0000-0001-6911-2260)
- Václav Havel (ORCID: https://orcid.org/0000-0002-6911-4669)
- Leia S. Stallings
- Vsevolod Katritch (ORCID: https://orcid.org/0000-0003-3883-4505)
- Michael Ansonoff
- Madalee G. Wulf (ORCID: https://orcid.org/0000-0002-7601-413X)
- Benjamin Bechand (ORCID: https://orcid.org/0000-0001-5237-2373)
- Amanda Hunkele (ORCID: https://orcid.org/0000-0002-2551-3035)
- Mu Yang (ORCID: https://orcid.org/0000-0002-1530-829X)
- Saheem A. Zaidi (ORCID: https://orcid.org/0000-0001-7531-3587)
- Rohini S. Ople (ORCID: https://orcid.org/0009-0006-1525-1883)
- Scot McIntosh (ORCID: https://orcid.org/0000-0001-9331-8648)
- Najah Abi‐Gerges (ORCID: https://orcid.org/0000-0001-9824-1694)
- Scott E. Hemby (ORCID: https://orcid.org/0000-0002-6987-1133)
- Jonathan A. Javitch (ORCID: https://orcid.org/0000-0001-7395-2967)
- Andrew C. Kruegel (ORCID: https://orcid.org/0000-0002-9156-8755)
- John E. Pintar (ORCID: https://orcid.org/0000-0001-5945-569X)
- Susruta Majumdar (ORCID: https://orcid.org/0000-0002-2931-3823)
- Alana Hodges
- Mel Nelson
Institutions
- High Point University (US)
- Rutgers, The State University of New Jersey (US)
- University of Southern California (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Health Sciences and Pharmacy (US)
- Washington University in St. Louis (US)
- New York Psychoanalytic Society and Institute (US)
- AnaBios (United States) (US)
- Environmental and Occupational Health Sciences Institute (US)
- Convergent Science (United States) (US)
- New York State Psychiatric Institute
- Saint Louis University (US)
- Columbia University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-20
- DOI
- https://doi.org/10.1038/s41467-024-51856-y
- Citations
- 14
- Primary Topic
- Alkaloids: synthesis and pharmacology
- Type
- article
- Field-Weighted Citation Impact
- 6.54
Funders
- Hope for Depression Research Foundation
- Memorial Sloan-Kettering Cancer Center
- High Point University
- Nadace Experientia
- Universidad de la República Uruguay
- National Institutes of Health
- National Institute of Mental Health
- National Institute on Drug Abuse
- National Cancer Institute