Detail
Article
Online article
FT
Medvik - BMC
  • Something wrong with this record ?

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

S. Bhowmik, J. Galeta, V. Havel, M. Nelson, A. Faouzi, B. Bechand, M. Ansonoff, T. Fiala, A. Hunkele, AC. Kruegel, JE. Pintar, S. Majumdar, JA. Javitch, D. Sames

. 2021 ; 12 (1) : 3858. [pub] 20210622

Language English Country Great Britain

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21025551

Grant support
P30 CA008748 NCI NIH HHS - United States
R01 DA046487 NIDA NIH HHS - United States
R21 AA026949 NIAAA NIH HHS - United States
R21 DA045884 NIDA NIH HHS - United States

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.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc21025551
003      
CZ-PrNML
005      
20211026133717.0
007      
ta
008      
211013s2021 xxk f 000 0|eng||
009      
AR
024    7_
$a 10.1038/s41467-021-23736-2 $2 doi
035    __
$a (PubMed)34158473
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxk
100    1_
$a Bhowmik, Srijita $u Department of Chemistry, Columbia University, New York, NY, USA
245    10
$a Site selective C-H functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy / $c S. Bhowmik, J. Galeta, V. Havel, M. Nelson, A. Faouzi, B. Bechand, M. Ansonoff, T. Fiala, A. Hunkele, AC. Kruegel, JE. Pintar, S. Majumdar, JA. Javitch, D. Sames
520    9_
$a 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.
650    _2
$a analgetika $x chemie $x farmakologie $7 D000700
650    _2
$a zvířata $7 D000818
650    _2
$a ethylenglykol $x chemie $7 D019855
650    _2
$a lidé $7 D006801
650    _2
$a myši knockoutované $7 D018345
650    _2
$a Mitragyna $x chemie $7 D032065
650    _2
$a chemické modely $7 D008956
650    _2
$a molekulární struktura $7 D015394
650    _2
$a rostlinné extrakty $x chemie $x farmakologie $7 D010936
650    _2
$a vazba proteinů $7 D011485
650    _2
$a receptory opiátové mu $x agonisté $x genetika $x metabolismus $7 D017450
650    _2
$a sekologanin-tryptaminové alkaloidy $x chemie $x farmakologie $7 D046948
655    _2
$a časopisecké články $7 D016428
655    _2
$a Research Support, N.I.H., Extramural $7 D052061
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Galeta, Juraj $u Department of Chemistry, Columbia University, New York, NY, USA $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB Prague), 160 00, Prague 6, Czech Republic
700    1_
$a Havel, Václav $u Department of Chemistry, Columbia University, New York, NY, USA
700    1_
$a Nelson, Melissa $u Department of Psychiatry, and Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, USA $u Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
700    1_
$a Faouzi, Abdelfattah $u Center for Clinical Pharmacology, St Louis College of Pharmacy and Washington University School of Medicine, St Louis, MO, 63110, USA $u University of California San Diego, La Jolla, CA, 92161, USA
700    1_
$a Bechand, Benjamin $u Department of Chemistry, Columbia University, New York, NY, USA
700    1_
$a Ansonoff, Mike $u Department of Neuroscience and Cell Biology, Rutgers University, New Jersey, NJ, 08854, USA
700    1_
$a Fiala, Tomas $u Department of Chemistry, Columbia University, New York, NY, USA $u Laboratory of Organic Chemistry, ETH Zürich, 8093, Zürich, Switzerland
700    1_
$a Hunkele, Amanda $u Center for Clinical Pharmacology, St Louis College of Pharmacy and Washington University School of Medicine, St Louis, MO, 63110, USA $u Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY, 10021, USA
700    1_
$a Kruegel, Andrew C $u Department of Chemistry, Columbia University, New York, NY, USA
700    1_
$a Pintar, John E $u Department of Neuroscience and Cell Biology, Rutgers University, New Jersey, NJ, 08854, USA
700    1_
$a Majumdar, Susruta $u Center for Clinical Pharmacology, St Louis College of Pharmacy and Washington University School of Medicine, St Louis, MO, 63110, USA
700    1_
$a Javitch, Jonathan A $u Department of Psychiatry, and Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, USA $u Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
700    1_
$a Sames, Dalibor $u Department of Chemistry, Columbia University, New York, NY, USA. ds584@columbia.edu $u NeuroTechnology Center at Columbia University, New York, NY, USA. ds584@columbia.edu $u The Zuckerman Mind Brain Behavior Institute at Columbia University, New York, NY, USA. ds584@columbia.edu
773    0_
$w MED00184850 $t Nature communications $x 2041-1723 $g Roč. 12, č. 1 (2021), s. 3858
856    41
$u https://pubmed.ncbi.nlm.nih.gov/34158473 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20211013 $b ABA008
991    __
$a 20211026133723 $b ABA008
999    __
$a ok $b bmc $g 1714555 $s 1146058
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2021 $b 12 $c 1 $d 3858 $e 20210622 $i 2041-1723 $m Nature communications $n Nat Commun $x MED00184850
GRA    __
$a P30 CA008748 $p NCI NIH HHS $2 United States
GRA    __
$a R01 DA046487 $p NIDA NIH HHS $2 United States
GRA    __
$a R21 AA026949 $p NIAAA NIH HHS $2 United States
GRA    __
$a R21 DA045884 $p NIDA NIH HHS $2 United States
LZP    __
$a Pubmed-20211013

Find record

Citation metrics

Logged in users only

Archiving options