Mitragynine pseudoindoxyl can be produced in the blood as a metabolite of 7-hydroxymitragynine.[2]
Pharmacology
Mitragynine pseudoindoxyl is a μ-opioid receptoragonist and δ-opioid receptorantagonist. It is a G proteinbiased agonist at the μ-opioid receptor, which may be responsible for its favorable side effect profile compared to conventional opioids.[3] 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.[4] 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.[5][6][7]
Chemistry
Mitragynine pseudoindoxyl was first accessible via biomimetic semisynthesis from mitragynine.[8][9][3] Total synthesis of an unnatural analogue was reported featuring an interrupted Ugi reaction as the key step.[10] Scalable and modular total synthesis of the natural product has also been accomplished using a chiral pool based strategy.[11][12] This study also demonstrated structural plasticity in biological systems.
^Jansen KL, Prast CJ (1988). "Ethnopharmacology of kratom and the Mitragyna alkaloids". Journal of Ethnopharmacology. 23 (1): 115–119. doi:10.1016/0378-8741(88)90121-3. PMID3419199.
^Takayama 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. doi:10.1021/jm010576e. PMID11960505.
^Yamamoto 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. doi:10.1016/S0306-3623(98)00265-1. PMID10428019.