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Site Selective C-H Functionalization of Mitragyna Alkaloids Reveals a Molecular Switch for Tuning Opioid Receptor Signaling Efficacy

preprint
submitted on 14.08.2020 and posted on 14.08.2020 by Srijita Bhowmik, Juraj Galeta, Vaclav Havel, Melissa Nelson, Abdelfattah Faouzi, Benjamin Bechand, Tomas Fiala, Amanda Hunkele, Andrew Kruegel, Susruta Majumdar, Jonathan A. Javitch,, Dalibor Sames

Mitragynine 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 developed a new synthetic method for selective functionalization of the unexplored C11 position of the mitragynine scaffold (C6 position in indole numbering) via the use of an indole-ethylene glycol adduct and subsequent iridium-catalyzed borylation. We discovered that C11 represents a key locant for fine-tuning opioid receptor signaling efficacy. In the 7-hydroxymitragynine (7OH) series, the high efficacy parent compound was transformed to an equipotent low 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 after systemic administration. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid medications with mitigated adverse effects.

History

Email Address of Submitting Author

sb3890@columbia.edu

Institution

Columbia University

Country

United States

ORCID For Submitting Author

0000-0001-5951-4557

Declaration of Conflict of Interest

S. B., J. G., V. H., A.C.K., J.A.J., S.M., and D.S., are named as inventors on patent applications related to mitragynine analogs. A.C.K., J.A.J. and D.S. are co-founders of Kures, Inc. SM is a co-founder of Sparian biosciences.

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