Mitragynine pseudoindoxyl is aμ-opioid receptoragonist andδ-opioid receptorantagonist. Animal studies have shown it causes reduced tolerance, withdrawal, and respiratory depression compared tomorphine.[3][4] Respiratory depression is the primary cause of death in the vast numbers of fatalities linked tofentanyl and other opioids. As an atypicalanalgesic it has a remarkably strong affinity for the MOR (0.087nM), compared with mitragynine at 7.24nM and 7-hydroxymitragynine at 13.5nM (lower figure means stronger binding). This substance has great potential on its own or as a starting point in the development of new and saferopioids.[4]
There are currently no documented overdose deaths as a result of usage of the substance.[4] However, its use in isolation is rare, and it is typically sold as a mixture, as in kratom, or alongside other kratom derivatives, which may be mislabeled.[2]
However, a 2020 review of these and more recent studies has found issues with some methods originally used to determine ligands to be G protein biased.Oliceridine, thought to be the prototypical G protein biased μ-opioid receptor agonist, along withPZM21, andbuprenorphine, were found to be unbiased. Rather, their lowintrinsic efficacy interfered with the results of highly amplified assays. There is also significant doubt about whetherβ-arrestin is truly responsible for the side effects of opioids, and positive results suggesting G-protein activation may still produce constipation, respiratory depression, and tolerance. In summary, mitragynine pseudoindoxyl may still have a better therapeutic window compared to other full agonists, including other putatively biased G-protein agonists, but more research is needed to quantify this effect, particularly in humans, and to elucidate its cause.[5]
Cryo-EM structures of μOR-Gi1 complex with mitragynine pseudoindoxyl andlofentanil (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.[3] 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]
Mitragynine pseudoindoxyl was first accessible via biomimetic semisynthesis from mitragynine.[9][10][4] Total synthesis of an unnatural analogue was reported featuring an interrupted Ugi reaction as the key step.[11] Scalable and modular total synthesis of the natural product has also been accomplished using a chiral pool based strategy.[12][13] 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.
