2. Academic Validation
  3. Oxidative Metabolism as a Modulator of Kratom's Biological Actions

Oxidative Metabolism as a Modulator of Kratom's Biological Actions

  • J Med Chem. 2021 Nov 25;64(22):16553-16572. doi: 10.1021/acs.jmedchem.1c01111.
Soumen Chakraborty 1,  Rajendra Uprety 2,  Samuel T Slocum 3,  Takeshi Irie 4,  Valerie Le Rouzic 2,  Xiaohai Li 5,  Lisa L Wilson 6,  Brittany Scouller 7,  Amy F Alder 7,  Andrew C Kruegel 8,  Michael Ansonoff 9,  Andras Varadi 2,  Shainnel O Eans 6,  Amanda Hunkele 2,  Abdullah Allaoa 2,  Sanjay Kalra 2,  Jin Xu 2,  Ying Xian Pan 2,  John Pintar 9,  Bronwyn M Kivell 7,  Gavril W Pasternak 2,  Michael D Cameron 5,  Jay P McLaughlin 6,  Dalibor Sames 8,  Susruta Majumdar 1
Affiliations

Affiliations

  • 1 Center for Clinical Pharmacology, University of Health Sciences & Pharmacy and Washington University School of Medicine, St. Louis, Missouri 63110, United States.
  • 2 Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York 10065, United States.
  • 3 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 4 Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York 10065, United States.
  • 5 Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida 33458, United States.
  • 6 Department of Pharmacodynamics, University of Florida, Gainesville, Florida 32610, United States.
  • 7 Centre for Biodiscovery, School of Biological Science, Victoria University of Wellington, Wellington 6012, New Zealand.
  • 8 Department of Chemistry, Columbia University, New York 10027, United States.
  • 9 Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-8021, United States.
PMID: 34783240 DOI: 10.1021/acs.jmedchem.1c01111
Abstract

The leaves of Mitragyna speciosa (kratom), a plant native to Southeast Asia, are increasingly used as a pain reliever and for attenuation of opioid withdrawal symptoms. Using the tools of Natural Products chemistry, chemical synthesis, and pharmacology, we provide a detailed in vitro and in vivo pharmacological characterization of the Alkaloids in kratom. We report that metabolism of kratom's major alkaloid, mitragynine, in mice leads to formation of (a) a potent mu Opioid Receptor Agonist antinociceptive agent, 7-hydroxymitragynine, through a CYP3A-mediated pathway, which exhibits reinforcing properties, inhibition of gastrointestinal (GI) transit and reduced hyperlocomotion, (b) a multifunctional mu agonist/delta-kappa antagonist, mitragynine pseudoindoxyl, through a CYP3A-mediated skeletal rearrangement, displaying reduced hyperlocomotion, inhibition of GI transit and reinforcing properties, and (c) a potentially toxic metabolite, 3-dehydromitragynine, through a non-CYP oxidation pathway. Our results indicate that the oxidative metabolism of the mitragynine template beyond 7-hydroxymitragynine may have implications in its overall pharmacology in vivo.

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