TY - JOUR
KW - Animals
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Oxidation-Reduction
KW - Receptors, Opioid, mu
KW - Secologanin Tryptamine Alkaloids/pharmacology
AU - S. Chakraborty
AU - R. Uprety
AU - S. T. Slocum
AU - T. Irie
AU - V. Le Rouzic
AU - X. Li
AU - L. L. Wilson
AU - B. Scouller
AU - A. F. Alder
AU - A. C. Kruegel
AU - M. Ansonoff
AU - A. Varadi
AU - S. O. Eans
AU - A. Hunkele
AU - A. Allaoa
AU - S. Kalra
AU - J. Xu
AU - Y. X. Pan
AU - J. Pintar
AU - B. M. Kivell
AU - G. W. Pasternak
AU - M. D. Cameron
AU - J. P. McLaughlin
AU - D. Sames
AU - S. Majumdar
A1 - 
AB - The leaves of Mitragyna speciosa (kratom), a plant native to Southeast Asia, are increasingly used as a pain reliever and for attenuation of opioid withdrawal symptoms. Using the tools of natural products chemistry, chemical synthesis, and pharmacology, we provide a detailed in vitro and in vivo pharmacological characterization of the alkaloids in kratom. We report that metabolism of kratom's major alkaloid, mitragynine, in mice leads to formation of (a) a potent mu opioid receptor agonist antinociceptive agent, 7-hydroxymitragynine, through a CYP3A-mediated pathway, which exhibits reinforcing properties, inhibition of gastrointestinal (GI) transit and reduced hyperlocomotion, (b) a multifunctional mu agonist/delta-kappa antagonist, mitragynine pseudoindoxyl, through a CYP3A-mediated skeletal rearrangement, displaying reduced hyperlocomotion, inhibition of GI transit and reinforcing properties, and (c) a potentially toxic metabolite, 3-dehydromitragynine, through a non-CYP oxidation pathway. Our results indicate that the oxidative metabolism of the mitragynine template beyond 7-hydroxymitragynine may have implications in its overall pharmacology in vivo.
AD - Center for Clinical Pharmacology, University of Health Sciences & Pharmacy and Washington University School of Medicine, St. Louis, Missouri 63110, United States.; Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York 10065, United States.; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York 10065, United States.; Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York 10065, United States.; Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida 33458, United States.; Department of Pharmacodynamics, University of Florida, Gainesville, Florida 32610, United States.; Centre for Biodiscovery, School of Biological Science, Victoria University of Wellington, Wellington 6012, New Zealand.; Centre for Biodiscovery, School of Biological Science, Victoria University of Wellington, Wellington 6012, New Zealand.; Department of Chemistry, Columbia University, New York 10027, United States.; Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-8021, United States.; Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York 10065, United States.; Department of Pharmacodynamics, University of Florida, Gainesville, Florida 32610, United States.; Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York 10065, United States.; Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York 10065, United States.; Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York 10065, United States.; Department of Neurology and Molecular Pharmacology, Memorial Slo(TRUNCATED)
BT - Journal of medicinal chemistry
C5 - Opioids & Substance Use
CP - 22
DO - 10.1021/acs.jmedchem.1c01111
IS - 22
JF - Journal of medicinal chemistry
LA - eng
M1 - Journal Article
N2 - The leaves of Mitragyna speciosa (kratom), a plant native to Southeast Asia, are increasingly used as a pain reliever and for attenuation of opioid withdrawal symptoms. Using the tools of natural products chemistry, chemical synthesis, and pharmacology, we provide a detailed in vitro and in vivo pharmacological characterization of the alkaloids in kratom. We report that metabolism of kratom's major alkaloid, mitragynine, in mice leads to formation of (a) a potent mu opioid receptor agonist antinociceptive agent, 7-hydroxymitragynine, through a CYP3A-mediated pathway, which exhibits reinforcing properties, inhibition of gastrointestinal (GI) transit and reduced hyperlocomotion, (b) a multifunctional mu agonist/delta-kappa antagonist, mitragynine pseudoindoxyl, through a CYP3A-mediated skeletal rearrangement, displaying reduced hyperlocomotion, inhibition of GI transit and reinforcing properties, and (c) a potentially toxic metabolite, 3-dehydromitragynine, through a non-CYP oxidation pathway. Our results indicate that the oxidative metabolism of the mitragynine template beyond 7-hydroxymitragynine may have implications in its overall pharmacology in vivo.
PY - 2021
SN - 1520-4804; 0022-2623; 0022-2623
SP - 16553
EP - 16572
EP - 
T1 - Oxidative Metabolism as a Modulator of Kratom's Biological Actions
T2 - Journal of medicinal chemistry
TI - Oxidative Metabolism as a Modulator of Kratom's Biological Actions
U1 - Opioids & Substance Use
U2 - 34783240
U3 - 10.1021/acs.jmedchem.1c01111
VL - 64
VO - 1520-4804; 0022-2623; 0022-2623
Y1 - 2021
Y2 - Nov 25
ER -