Mitragynine pseudoindoxyl is a
μ opioid receptoragonist and
δ opioid receptorantagonist and acts as a
G proteinbiased agonist at μ opioid receptors and possesses a favourable side effect profile compared to conventional
opioids.[4] Cryo-EM structures of μOR-Gi1 complex with mitragynine pseudoindoxyl and lofentanil (one of the most potent opioids) revealed that the two ligands engage distinct subpockets, and molecular dynamics simulations showed additional differences in the binding site that promote distinct active-state conformations on the intracellular side of the receptor where G proteins and β-arrestins bind.[5] Importantly, studies have shown that oxidative metabolism is capable of transforming mitragynine (the main alkaloid in kratom) into mitragynine pseudoindoxyl in two steps, which is likely to influence kratom's complex pharmacological effects.[6][7][8]
Chemistry
Mitragynine pseudoindoxyl was first accessible via biomimetic semisynthesis from mitragynine.[2][3][4] Total synthesis of an unnatural analogue was reported featuring an interrupted Ugi reaction as the key step.[9] Scalable and modular total synthesis of the natural product has been also accomplished using a chiral pool based strategy.[10][11] This study also demonstrated structural plasticity in biological systems.
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abTakayama H, Ishikawa H, Kurihara M, Kitajima M, Aimi N, Ponglux D, et al. (April 2002). "Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands". Journal of Medicinal Chemistry. 45 (9): 1949–1956.
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PMID11960505.
^
abYamamoto LT, Horie S, Takayama H, Aimi N, Sakai S, Yano S, et al. (July 1999). "Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa". General Pharmacology. 33 (1): 73–81.
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10.1016/S0306-3623(98)00265-1.
PMID10428019.
^Qu Q, Huang W, Aydin D, Paggi JM, Seven AB, Wang H, et al. (April 2023). "Insights into distinct signaling profiles of the µOR activated by diverse agonists". Nature Chemical Biology. 19 (4): 423–430.
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10.1038/s41589-022-01208-y.
PMID36411392.
S2CID245021836.