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Papers of the Week

Papers: 19 Jun 2021 - 25 Jun 2021

Animal Studies, Human Studies, Pharmacology/Drug Development

2021 Jun 22

Nat Commun



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


Bhowmik S, Galeta J, Havel V, Nelson M, Faouzi A, Bechand B, Ansonoff M, Fiala T, Hunkele A, Kruegel AC, Pintar JE, Majumdar S, Javitch JA, Sames D
Nat Commun. 2021 Jun 22; 12(1):3858.
PMID: 34158473.


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.