Chemistry:Mitragynine pseudoindoxyl

From HandWiki
Short description: Opioid analgesic compound

Mitragynine pseudoindoxyl
Clinical data
Other namesSpiro(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)-
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC23H30N2O5
Molar mass414.502 g·mol−1
3D model (JSmol)

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]

Pharmacology

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 an atypical analgesic 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 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]

As a possible G protein biased agonist

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]

Chemistry

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.

See also

References

  1. ↑ "Ethnopharmacology of kratom and the Mitragyna alkaloids". Journal of Ethnopharmacology 23 (1): 115–119. 1988. doi:10.1016/0378-8741(88)90121-3. PMID 3419199. 
  2. ↑ 2.0 2.1 "Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy". ACS Pharmacology & Translational Science 3 (6): 1063–1068. December 2020. doi:10.1021/acsptsci.0c00075. PMID 33344889. 
  3. ↑ 3.0 3.1 "Insights into distinct signaling profiles of the µOR activated by diverse agonists". Nature Chemical Biology 19 (4): 423–430. April 2023. doi:10.1038/s41589-022-01208-y. PMID 36411392. 
  4. ↑ 4.0 4.1 4.2 4.3 "Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2". Journal of Medicinal Chemistry 59 (18): 8381–8397. September 2016. doi:10.1021/acs.jmedchem.6b00748. PMID 27556704. 
  5. ↑ "Critical Assessment of G Protein-Biased Agonism at the μ-Opioid Receptor" (in English). Trends in Pharmacological Sciences 41 (12): 947–959. December 2020. doi:10.1016/j.tips.2020.09.009. PMID 33097283. 
  6. ↑ "Unveiling 7-Hydroxymitragynine as the Key Active Metabolite of Mitragynine and the Promise for Creating Novel Pain Relievers". ACS Central Science 5 (6): 936–938. June 2019. doi:10.1021/acscentsci.9b00462. PMID 31263752. 
  7. ↑ "Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy". ACS Pharmacology & Translational Science 3 (6): 1063–1068. December 2020. doi:10.1021/acsptsci.0c00075. PMID 33344889. 
  8. ↑ "Oxidative Metabolism as a Modulator of Kratom's Biological Actions". Journal of Medicinal Chemistry 64 (22): 16553–16572. November 2021. doi:10.1021/acs.jmedchem.1c01111. PMID 34783240. 
  9. ↑ "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. April 2002. doi:10.1021/jm010576e. PMID 11960505. 
  10. ↑ "Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa". General Pharmacology 33 (1): 73–81. July 1999. doi:10.1016/S0306-3623(98)00265-1. PMID 10428019. 
  11. ↑ "A chemical synthesis of 11-methoxy mitragynine pseudoindoxyl featuring the interrupted Ugi reaction". Chemical Science 3 (9): 2849–2852. September 2012. doi:10.1039/C2SC20669B. PMID 23878716. 
  12. ↑ "Syntheses and structural plasticity of kratom pseudoindoxyl metabolites" (in en). ChemRxiv. 2023-02-02. doi:10.26434/chemrxiv-2023-62vzz-v2. https://chemrxiv.org/engage/chemrxiv/article-details/63dab15989c04b6693c92cba. 
  13. ↑ "Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl Metabolites". Angewandte Chemie 62 (35). August 2023. doi:10.1002/anie.202303700. PMID 37332089. Bibcode: 2023ACIE...62E3700A. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Mitragynine_pseudoindoxyl&oldid=4245757"