Site selective C–H functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy

Srijita Bhowmik, Juraj Galeta, Václav Havel, Melissa Nelson, Abdelfattah Faouzi, Benjamin Bechand, Mike Ansonoff, Tomas Fiala, Amanda Hunkele, Andrew C. Kruegel, John. E. Pintar, Susruta Majumdar, Jonathan A. Javitch and Dalibor Sames ()
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Srijita Bhowmik: Columbia University
Juraj Galeta: Columbia University
Václav Havel: Columbia University
Melissa Nelson: Columbia University
Abdelfattah Faouzi: St Louis College of Pharmacy and Washington University School of Medicine
Benjamin Bechand: Columbia University
Mike Ansonoff: Rutgers University
Tomas Fiala: Columbia University
Amanda Hunkele: St Louis College of Pharmacy and Washington University School of Medicine
Andrew C. Kruegel: Columbia University
John. E. Pintar: Rutgers University
Susruta Majumdar: St Louis College of Pharmacy and Washington University School of Medicine
Jonathan A. Javitch: Columbia University
Dalibor Sames: Columbia University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Mitragynine (MG) is the most abundant alkaloid component of the psychoactive plant material “kratom”, which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We have developed a synthetic method for selective functionalization of the unexplored C11 position of the MG scaffold (C6 position in indole numbering) via the use of an indole-ethylene glycol adduct and subsequent iridium-catalyzed borylation. Through this work we discover that C11 represents a key locant for fine-tuning opioid receptor signaling efficacy. 7-Hydroxymitragynine (7OH), the parent compound with low efficacy on par with buprenorphine, is transformed to an even lower efficacy agonist by introducing a fluorine substituent in this position (11-F-7OH), as demonstrated in vitro at both mouse and human mu opioid receptors (mMOR/hMOR) and in vivo in mouse analgesia tests. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid medications with mitigated adverse effects.

Date: 2021
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DOI: 10.1038/s41467-021-23736-2

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