2. Academic Validation
  3. Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models

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

  • Nat Commun. 2024 Sep 20;15(1):8118. doi: 10.1038/s41467-024-51856-y.
Václav Havel # 1,  Andrew C Kruegel # 1,  Benjamin Bechand # 1,  Scot McIntosh 2,  Leia Stallings 2,  Alana Hodges 2,  Madalee G Wulf 1,  Mel Nelson 3 4 5,  Amanda Hunkele 6 7,  Michael Ansonoff 8,  John E Pintar 8 9,  Christopher Hwu 1,  Rohini S Ople 7 10,  Najah Abi-Gerges 11,  Saheem A Zaidi 12 13,  Vsevolod Katritch 12 13,  Mu Yang 14,  Jonathan A Javitch 3 4 5,  Susruta Majumdar 6 7 10,  Scott E Hemby 2,  Dalibor Sames 15 16
Affiliations

Affiliations

  • 1 Department of Chemistry, Columbia University, New York, NY, 10027, USA.
  • 2 Department of Basic Pharmaceutical Sciences, Fred Wilson School of Pharmacy, High Point University, High Point, NC, 27268, USA.
  • 3 Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, 10032, USA.
  • 4 Department of Psychiatry, Columbia University, New York, NY, 10032, USA.
  • 5 Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, 10032, USA.
  • 6 Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 7 Center for Clinical Pharmacology, University of Health Sciences & Pharmacy at St Louis and Washington University School of Medicine, St Louis, MO, 63110, USA.
  • 8 Department of Neuroscience and Cell Biology, Rutgers University, Piscataway, NJ, 08854, USA.
  • 9 Rutgers Addiction Research Center, Brain Health Institute, Rutgers University, Piscataway, NJ, 08854, USA.
  • 10 Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, 63110, USA.
  • 11 AnaBios Corporation, 1155 Island Ave, Suite 200, San Diego, CA, 92101, USA.
  • 12 Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, 90089, USA.
  • 13 Department of Chemistry, Bridge Institute, Michelson Center for Convergent Sciences, University of Southern California, Los Angeles, CA, 90089, USA.
  • 14 Mouse Neurobehavioral Core facility, Columbia University Irving Medical Center, New York, NY, 10032, USA.
  • 15 Department of Chemistry, Columbia University, New York, NY, 10027, USA. ds584@columbia.edu.
  • 16 The Zuckerman Mind Brain Behavior Institute at Columbia University, New York, NY, USA. ds584@columbia.edu.
  • # Contributed equally.
PMID: 39304653 DOI: 10.1038/s41467-024-51856-y
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.

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