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Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

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    Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators
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    † †Department of Chemistry, ‡Department of Psychiatry, and §Department of Pharmacology, Columbia University, New York, New York 10027, United States
    ∥ Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
    ⊥ Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States
    ∇ Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, United States
    *[email protected]
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    Cite this: J. Am. Chem. Soc. 2016, 138, 21, 6754–6764
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    https://doi.org/10.1021/jacs.6b00360
    Published May 18, 2016
    Copyright © 2016 American Chemical Society
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    Mu-opioid receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is associated with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of the Southeast Asian plant Mitragyna speciosa, represented by the prototypical member mitragynine, are an unusual class of opioid receptor modulators with distinct pharmacological properties. Here we describe the first receptor-level functional characterization of mitragynine and related natural alkaloids at the human mu-, kappa-, and delta-opioid receptors. These results show that mitragynine and the oxidized analogue 7-hydroxymitragynine, are partial agonists of the human mu-opioid receptor and competitive antagonists at the kappa- and delta-opioid receptors. We also show that mitragynine and 7-hydroxymitragynine are G-protein-biased agonists of the mu-opioid receptor, which do not recruit β-arrestin following receptor activation. Therefore, the Mitragyna alkaloid scaffold represents a novel framework for the development of functionally biased opioid modulators, which may exhibit improved therapeutic profiles. Also presented is an enantioselective total synthesis of both (−)-mitragynine and its unnatural enantiomer, (+)-mitragynine, employing a proline-catalyzed Mannich–Michael reaction sequence as the key transformation. Pharmacological evaluation of (+)-mitragynine revealed its much weaker opioid activity. Likewise, the intermediates and chemical transformations developed in the total synthesis allowed the elucidation of previously unexplored structure–activity relationships (SAR) within the Mitragyna scaffold. Molecular docking studies, in combination with the observed chemical SAR, suggest that Mitragyna alkaloids adopt a binding pose at the mu-opioid receptor that is distinct from that of classical opioids.

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