Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models Journal Article
| Authors: | Havel, V.; Kruegel, A. C.; Bechand, B.; McIntosh, S.; Stallings, L.; Hodges, A.; Wulf, M. G.; Nelson, M.; Hunkele, A.; Ansonoff, M.; Pintar, J. E.; Hwu, C.; Ople, R. S.; Abi-Gerges, N.; Zaidi, S. A.; Katritch, V.; Yang, M.; Javitch, J. A.; Majumdar, S.; Hemby, S. E.; Sames, D. |
| Article Title: | Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models |
| 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. © The Author(s) 2024. |
| Keywords: | controlled study; human cell; genetics; nonhuman; comparative study; mouse; phenotype; animal; metabolism; animals; opiate; sedation; luciferase; animal experiment; animal model; drug effect; risk assessment; disease model; narcotic analgesic agent; rat; molecular analysis; rats; rodent; pharmacophore; catalysis; rats, sprague-dawley; morphine; analgesics, opioid; opioid-related disorders; drug therapy; disease models, animal; x ray crystallography; alkaloids; mental health; metabolite; brain region; dopaminergic nerve cell; palladium; locomotion; sprague dawley rat; drug use; hyperalgesia; tail flick test; aversive behavior; fentanyl; 3,4 dichloro n methyl n [2 (1 pyrrolidinyl)cyclohexyl]benzeneacetamide; diamorphine; analgesic activity; opiate addiction; physical stimulation; delta opiate receptor; drug; numerical model; limit of detection; antinociception; alkaloid; myocytes, cardiac; kappa opiate receptor; drug self administration; humans; human; male; female; article; receptors, opioid, kappa; nociceptin receptor; kappa opiate receptor agonist; ec50; nanobody; cardiac muscle cell; ibogaine; noribogaine; bioluminescence resonance energy transfer; mechanical hypersensitivity; opioid induced hyperalgesia |
| Journal Title: | Nature Communications |
| Volume: | 15 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-09-20 |
| Start Page: | 8118 |
| Language: | English |
| DOI: | 10.1038/s41467-024-51856-y |
| PUBMED: | 39304653 |
| PROVIDER: | scopus |
| PMCID: | PMC11415492 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Scopus |
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