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

Andrew C. Kruegel, Madalee M. Gassaway, Abhijeet Kapoor, A. Váradi, Susruta Majumdar, Marta Filizola, Jonathan A. Javitch, Dalibor Sames

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)6754-6764
Number of pages11
JournalJournal of the American Chemical Society
Volume138
Issue number21
DOIs
Publication statusPublished - Jun 1 2016

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Mitragyna
Artificial Receptors
Alkaloids
Opioid Receptors
Modulators
mu Opioid Receptor
Opioid Analgesics
Scaffolds
kappa Opioid Receptor
delta Opioid Receptor
Structure-Activity Relationship
Enantiomers
Pharmacology
Arrestin
Chemical activation
Narcotic Antagonists
Proteins
Therapeutic Uses
Pain Management
mitragynine

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids : Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators. / Kruegel, Andrew C.; Gassaway, Madalee M.; Kapoor, Abhijeet; Váradi, A.; Majumdar, Susruta; Filizola, Marta; Javitch, Jonathan A.; Sames, Dalibor.

In: Journal of the American Chemical Society, Vol. 138, No. 21, 01.06.2016, p. 6754-6764.

Research output: Contribution to journalArticle

Kruegel, Andrew C. ; Gassaway, Madalee M. ; Kapoor, Abhijeet ; Váradi, A. ; Majumdar, Susruta ; Filizola, Marta ; Javitch, Jonathan A. ; Sames, Dalibor. / Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids : Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators. In: Journal of the American Chemical Society. 2016 ; Vol. 138, No. 21. pp. 6754-6764.
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