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Other names | Spiro(2H-indole-2,1'(5'H)-indolizine)-7'-acetic acid, 6'-ethyl-1,2',3,3',6',7',8',8'a-octahydro-4-methoxy-alpha-(methoxymethylene)-3-oxo-, methyl ester, (alphaE,1'S,6'S,7'S,8'as)- |
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Chemical and physical data | |
Formula | C23H30N2O5 |
Molar mass | 414.502 g·mol−1 |
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Mitragynine pseudoindoxyl is a rearrangement product of 7-hydroxymitragynine, an active metabolite of mitragynine. [1]
Mitragynine pseudoindoxyl can be produced in the blood as a metabolite of 7-hydroxymitragynine. [2]
Mitragynine pseudoindoxyl is a μ-opioid receptor agonist and δ-opioid receptor antagonist. Animal studies have shown it causes reduced tolerance, withdrawal, and respiratory depression compared to morphine. [3] [4] Respiratory depression is the primary cause of death in the vast numbers of fatalities linked to fentanyl and other opioids. As a potent analgesic with a long half-life [ verification needed ], it has great potential on its own or as a starting point in the development of safer opioids. [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]
Studies have shown it may be a G protein biased agonist at the μ-opioid receptor; this may explain the more favorable side effect profile found in some research. [3] [4] [ verification needed ]
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 with PZM21, and buprenorphine, were found to be unbiased. Rather, their low intrinsic efficacy interfered with the results of highly amplified assays. There is also significant doubt about whether β-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 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. [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.