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.
Srijita Bhowmik Columbia University
download asset C11 Mitragynine Manuscript.07.30.2020.pdf 0.83 MB [opens in a new tab] cloud_download
pdf : 0.83 MB
download asset Supplementary Information.07.30.2020.pdf 7 MB [opens in a new tab] cloud_download
pdf : 7 MB