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.

• MeSH
• analgetika chemie   farmakologie   MeSH
• chemické modely MeSH
• ethylenglykol chemie   MeSH
• lidé MeSH
• Mitragyna chemie   MeSH
• molekulární struktura MeSH
• myši knockoutované MeSH
• myši MeSH
• receptory opiátové mu agonisté   genetika   metabolismus   MeSH
• rostlinné extrakty chemie   farmakologie   MeSH
• sekologanin-tryptaminové alkaloidy chemie   farmakologie   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• 7-hydroxymitragynine MeSH Prohlížeč
• analgetika MeSH
• ethylenglykol MeSH
• receptory opiátové mu MeSH
• rostlinné extrakty MeSH
• sekologanin-tryptaminové alkaloidy MeSH