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

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 <i>Mitragyna speciosa</i>, 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 <i>Mitragyna</i> 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 <i>Mitragyna</i> scaffold. Molecular docking studies, in combination with the observed chemical SAR, suggest that <i>Mitragyna</i> alkaloids adopt a binding pose at the mu-opioid receptor that is distinct from that of classical opioids