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Exploring the Chemistry of Alkaloids from Malaysian Mitragyna speciosa (Kratom) and the Role of Oxindoles on Human Opioid Receptors

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Nat. Prod. 2021, 84, 4, 1034-1043
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    Exploring the Chemistry of Alkaloids from Malaysian Mitragyna speciosa (Kratom) and the Role of Oxindoles on Human Opioid Receptors
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    • Nelson Jeng-Yeou Chear
      Nelson Jeng-Yeou Chear
      Centre for Drug Research, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia
      Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
      More by Nelson Jeng-Yeou Chear
    • Francisco León
      Francisco León
      Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
      More by Francisco León
      Orcidhttp://orcid.org/0000-0002-5064-2381
    • Abhisheak Sharma
      Abhisheak Sharma
      Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
      Translational Drug Development Core, Clinical and Translational Sciences Institute, University of Florida, Gainesville, Florida 32610, United States
      More by Abhisheak Sharma
      Orcidhttp://orcid.org/0000-0003-0553-4039
    • Siva Rama Raju Kanumuri
      Siva Rama Raju Kanumuri
      Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
      Translational Drug Development Core, Clinical and Translational Sciences Institute, University of Florida, Gainesville, Florida 32610, United States
      More by Siva Rama Raju Kanumuri
    • Grant Zwolinski
      Grant Zwolinski
      Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
      More by Grant Zwolinski
    • Khalil A. Abboud
      Khalil A. Abboud
      Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States
      More by Khalil A. Abboud
    • Darshan Singh
      Darshan Singh
      Centre for Drug Research, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia
      More by Darshan Singh
    • Luis F. Restrepo
      Luis F. Restrepo
      Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
      More by Luis F. Restrepo
    • Avi Patel
      Avi Patel
      Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
      More by Avi Patel
    • Takato Hiranita
      Takato Hiranita
      Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
      More by Takato Hiranita
    • Surash Ramanathan
      Surash Ramanathan
      Centre for Drug Research, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia
      More by Surash Ramanathan
    • Aidan J. Hampson
      Aidan J. Hampson
      Division of Therapeutics and Medical Consequences, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland 20892, United States
      More by Aidan J. Hampson
    • Lance R. McMahon
      Lance R. McMahon
      Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
      More by Lance R. McMahon
    • Christopher R. McCurdy*
      Christopher R. McCurdy
      Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
      Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
      Translational Drug Development Core, Clinical and Translational Sciences Institute, University of Florida, Gainesville, Florida 32610, United States
      *Email: [email protected]
      More by Christopher R. McCurdy
      Orcidhttp://orcid.org/0000-0001-8695-2915
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    Journal of Natural Products

    Cite this: J. Nat. Prod. 2021, 84, 4, 1034–1043
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    https://doi.org/10.1021/acs.jnatprod.0c01055
    Published February 26, 2021
    Copyright © 2021 American Chemical Society and American Society of Pharmacognosy
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    Abstract

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    Ten indole and oxindole alkaloids (1–10) were isolated from the freshly collected leaves of Malaysian Mitragyna speciosa (Kratom). The chemical structures of these compounds were established on the basis of extensive 1D and 2D NMR and HRMS data analysis. The spectroscopic data of mitragynine oxindole B (4) are reported herein for the first time. The spatial configuration of mitragynine oxindole B (4) was confirmed by single-crystal X-ray diffraction. Simultaneous quantification of the isolated alkaloids in the M. speciosa leaf specimens collected from different locations in the northern region of Peninsular Malaysia was also performed using UPLC-MS/MS. The oxindole alkaloids (1–4) and the indole alkaloid (10) were assessed for binding affinity at opioid receptors. Corynoxine (1) showed high binding affinity to μ-opioid receptors with a Ki value of 16.4 nM. Further, corynoxine (1) was 1.8-fold more potent than morphine in rats subjected to a nociceptive hot plate assay. These findings have important implications for evaluating the combined effects of the minor oxindole alkaloids in the overall therapeutic activity of M. speciosa.

    Copyright © 2021 American Chemical Society and American Society of Pharmacognosy

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jnatprod.0c01055.

    • Map and table describing the sampling locations of M. speciosa specimens in Peninsular Malaysia; description of the putative biosynthesis of main alkaloids in M. speciosa; 1H and 13C NMR for compounds 1–3 and 10 and 1H, 13C, and 2D NMR spectra of compound 4; ESI-TOF-MS/MS spectra of compounds 4 and 10; MRM chromatograms of test compounds 1–14 and internal standard; tables summarizing the compound parameter for tested alkaloids 1–14, internal standard for UPLC/MS/MS analysis (PDF)

    • Crystallographic data of compound 4 (CIF)

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    Cite this: J. Nat. Prod. 2021, 84, 4, 1034–1043
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    https://doi.org/10.1021/acs.jnatprod.0c01055
    Published February 26, 2021
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