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Modified Akuamma Alkaloids with Increased Potency at the Mu-opioid Receptor

  • Madeline R. Hennessy
    Madeline R. Hennessy
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, Illinois 60612, United States
  • Anna M. Gutridge
    Anna M. Gutridge
    Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States
  • Alexander R. French
    Alexander R. French
    Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States
    Departments of Neurology and Bioengineering, University of Illinois Chicago, Chicago, Illinois 60612, United States
  • Elizabeth S. Rhoda
    Elizabeth S. Rhoda
    Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States
  • Yazan J. Meqbil
    Yazan J. Meqbil
    Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States
  • Meghna Gill
    Meghna Gill
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, Illinois 60612, United States
    More by Meghna Gill
  • Yavnika Kashyap
    Yavnika Kashyap
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, Illinois 60612, United States
  • Kevin Appourchaux
    Kevin Appourchaux
    Center for Clinical Pharmacology, University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine, St. Louis, Missouri 63110, United States
  • Barnali Paul
    Barnali Paul
    Center for Clinical Pharmacology, University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine, St. Louis, Missouri 63110, United States
    More by Barnali Paul
  • Zaijie Jim Wang
    Zaijie Jim Wang
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, Illinois 60612, United States
    Departments of Neurology and Bioengineering, University of Illinois Chicago, Chicago, Illinois 60612, United States
  • Richard M. van Rijn
    Richard M. van Rijn
    Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States
    Purdue Institute for Drug Discovery, West Lafayette, Indiana 47907, United States
    Purdue Institute for Integrative Neuroscience, West Lafayette, Indiana 47907, United States
    Purdue Interdisciplinary Life Sciences Graduate Program, Purdue University, West Lafayette, Indiana 47907, United States
  • , and 
  • Andrew P. Riley*
    Andrew P. Riley
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, Illinois 60612, United States
    *Email: [email protected]
Cite this: J. Med. Chem. 2023, 66, 5, 3312–3326
Publication Date (Web):February 24, 2023
https://doi.org/10.1021/acs.jmedchem.2c01707
Copyright © 2023 American Chemical Society

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    Supporting Info (4)»

    Abstract

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    Akuammine (1) and pseudoakuammigine (2) are indole alkaloids found in the seeds of the akuamma tree (Picralima nitida). Both alkaloids are weak agonists of the mu opioid receptor (μOR); however, they produce minimal effects in animal models of antinociception. To probe the interactions of 1 and 2 at the opioid receptors, we have prepared a collection of 22 semisynthetic derivatives. Evaluation of this collection at the μOR and kappa opioid receptor (κOR) revealed structural-activity relationship trends and derivatives with improved potency at the μOR. Most notably, the introduction of a phenethyl moiety to the N1 of 2 produces a 70-fold increase in potency and a 7-fold increase in selectivity for the μOR. The in vitro potency of this compound resulted in increased efficacy in the tail-flick and hot-plate assays of antinociception. The improved potency of these derivatives highlights the promise of exploring natural product scaffolds to probe the opioid receptors.

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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.jmedchem.2c01707.

    • Additional supplementary figures (Figures S1–2), HPLC chromatograph of compound 33, and 1H NMR and 13C NMR spectra for compounds 733 (PDF)

    • Molecular formula strings and associated activity for compounds 1, 2, 58, 1029, and 3133 (CSV)

    • Docked binding pose for compound 33 (PDB)

    • Docked binding pose for compound 19 (PDB)

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