Oxidative Metabolism as a Modulator of Kratom's Biological Actions.
Oxidative Metabolism as a Modulator of Kratom's Biological Actions.
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DOI：
10.1021/acs.jmedchem.1c01111
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发表时间：
2021-11-25
影响因子：
7.3
通讯作者：
Majumdar S
中科院分区：
文献类型：
--
作者：
Chakraborty S;Uprety R;Slocum ST;Irie T;Le Rouzic V;Li X;Wilson LL;Scouller B;Alder AF;Kruegel AC;Ansonoff M;Varadi A;Eans SO;Hunkele A;Allaoa A;Kalra S;Xu J;Pan YX;Pintar J;Kivell BM;Pasternak GW;Cameron MD;McLaughlin JP;Sames D;Majumdar S
光叶是一种原产于东南亚的植物，其叶越来越多地被用作止痛药和减轻阿片类药物的戒断症状。利用天然产物化学、化学合成和药理学等手段，对Krtom中的生物碱进行了详细的体外和体内药理研究。我们报道了KrATOM的主要生物碱米特拉宁在小鼠体内的代谢导致：(A)有效的MU阿片受体激动剂7-羟基米拉吉宁通过CYP3A介导的途径形成，它表现出增强特性，抑制胃肠道(GI)转运和减少过度运动；(B)多功能MU激动剂/增量-kappa拮抗剂米特拉宁伪吲哚青基，通过CYP3A介导的骨骼重排，显示出减少的过度运动，抑制GI水合转运和增强特性，以及(C)潜在的毒性代谢物3-去米托吉宁，通过非CYP氧化途径。我们的结果表明，除7-羟基三氮杂环氨酸外，三尖杉酯碱模板的氧化代谢可能在其体内的整体药理学中有一定的意义。
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.
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影响因子：
3.4
作者：
Henningfield JE;Fant RV;Wang DW
通讯作者：
Wang DW
基于carfentanyy模板的新型μ-δ阿片受体异构体性激动剂的合成和药理学。
影响因子：
7.3
作者：
Faouzi A;Uprety R;Gomes I;Massaly N;Keresztes AI;Le Rouzic V;Gupta A;Zhang T;Yoon HJ;Ansonoff M;Allaoa A;Pan YX;Pintar J;Morón JA;Streicher JM;Devi LA;Majumdar S
通讯作者：
Majumdar S
影响因子：
2.9
作者：
Chakraborty S;Majumdar S
通讯作者：
Majumdar S
影响因子：
7.3
作者：
Eans, Shainnel O.;Ganno, Michelle L.;Nefzi, Adel
通讯作者：
Nefzi, Adel
影响因子：
3.1
作者：
Hayes, John A.;Eccles, Kevin S.;Moynihan, Humphrey A.
通讯作者：
Moynihan, Humphrey A.