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

J 2021

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

BHOWMIK, Srijita; Juraj GALETA; Vaclav HAVEL; Melissa NELSON; Abdelfattah FAOUZI et al.

Základní údaje

Originální název

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

Autoři

Vydání

Nature Communications, London, Nature Publishing Group, 2021, 2041-1723

Další údaje

Typ výsledku

Článek v odborném periodiku

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 17.694

Označené pro přenos do RIV

DOI

https://doi.org/10.1038/s41467-021-23736-2

Štítky

ne MU, ne RIV

Změněno: 17. 2. 2025 10:43, Mgr. Pavla Foltynová, Ph.D.

Anotace

V originále

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. Mitragynine (MG) is an indole alkaloid from kratom plant that binds opioid receptors and as such presents a scaffold for the development of atypical opioid receptor modulators. Here, the authors report a synthetic method for selective functionalization of the C11 position of MG, and show that this position is essential for fine-tuning opioid receptor signaling efficacy.

Citovat

BHOWMIK, Srijita; Juraj GALETA; Vaclav HAVEL; Melissa NELSON; Abdelfattah FAOUZI; Benjamin BECHAND; Mike ANSONOFF; Tomáš FIALA; Amanda HUNKELE; Andrew C KRUEGEL; John E PINTAR; Susruta MAJUMDAR; Jonathan A JAVITCH a Dalibor SAMES. Site selective C–H functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy. Nature Communications. London: Nature Publishing Group, 2021, roč. 12, č. 1, 14 s. ISSN 2041-1723. Dostupné z: https://doi.org/10.1038/s41467-021-23736-2.

@article{2477818,
   author = {Bhowmik, Srijita and Galeta, Juraj and Havel, Vaclav and Nelson, Melissa and Faouzi, Abdelfattah and Bechand, Benjamin and Ansonoff, Mike and Fiala, Tomáš and Hunkele, Amanda and Kruegel, Andrew C and Pintar, John E and Majumdar, Susruta and Javitch, Jonathan A and Sames, Dalibor},
   article_location = {London},
   article_number = {1},
   doi = {https://doi.org/10.1038/s41467-021-23736-2},
   issn = {2041-1723},
   journal = {Nature Communications},
   note = {nevzniklo na MU},
   title = {Site selective C–H functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy},
   volume = {12},
   year = {2021}
}

TY  - JOUR
ID  - 2477818
AU  - Bhowmik, Srijita - Galeta, Juraj - Havel, Vaclav - Nelson, Melissa - Faouzi, Abdelfattah - Bechand, Benjamin - Ansonoff, Mike - Fiala, Tomáš - Hunkele, Amanda - Kruegel, Andrew C - Pintar, John E - Majumdar, Susruta - Javitch, Jonathan A - Sames, Dalibor
PY  - 2021
TI  - Site selective C–H functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy
JF  - Nature Communications
VL  - 12
IS  - 1
PB  - Nature Publishing Group
SN  - 20411723
N1  - nevzniklo na MU
N2  - 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. Mitragynine (MG) is an indole alkaloid from kratom plant that binds opioid receptors and as such presents a scaffold for the development of atypical opioid receptor modulators. Here, the authors report a synthetic method for selective functionalization of the C11 position of MG, and show that this position is essential for fine-tuning opioid receptor signaling efficacy.
ER  -

BHOWMIK, Srijita; Juraj GALETA; Vaclav HAVEL; Melissa NELSON; Abdelfattah FAOUZI; Benjamin BECHAND; Mike ANSONOFF; Tomáš FIALA; Amanda HUNKELE; Andrew C KRUEGEL; John E PINTAR; Susruta MAJUMDAR; Jonathan A JAVITCH a Dalibor SAMES. Site selective C–H functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy. \textit{Nature Communications}. London: Nature Publishing Group, 2021, roč.~12, č.~1, 14 s. ISSN~2041-1723. Dostupné z: https://doi.org/10.1038/s41467-021-23736-2.

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