Oxidative Metabolism as a Modulator of Kratom’s Biological Actions
| Autor: | Bronwyn M. Kivell, Shainnel O. Eans, Abdullah Allaoa, András Váradi, Lisa L. Wilson, Gavril W. Pasternak, Rajendra Uprety, Andrew C. Kruegel, John E. Pintar, Xiaohai Li, Samuel T. Slocum, Takeshi Irie, Jay P. McLaughlin, Brittany Scouller, Amy F. Alder, Michael D. Cameron, Sanjay Kalra, Ying-Xian Pan, Amanda Hunkele, Susruta Majumdar, Michael Ansonoff, Valerie Le Rouzic, Dalibor Sames, Soumen Chakraborty, Jin Xu |
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| Rok vydání: | 2021 |
| Předmět: |
Mice
Knockout Agonist biology medicine.drug_class Metabolite Alkaloid Mitragyna speciosa Receptors Opioid mu Antagonist Pharmacology biology.organism_classification Secologanin Tryptamine Alkaloids Article Mitragynine pseudoindoxyl Mice Inbred C57BL Mice chemistry.chemical_compound chemistry Mitragynine Drug Discovery medicine Animals Molecular Medicine μ-opioid receptor Oxidation-Reduction |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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