Mitragynine pseudoindoxyl

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Mitragynine pseudoindoxyl
Mitragynine-pseudoindoxyl.svg
Mitragynine pseudoindoxyl.png
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
  • methyl (2E)-2-[(1′S,6′S,7′S,8′aS)-6′-ethyl-4-methoxy-3-oxo-1,2′,3,3′,6′,7′,8′,8′a-octahydro-5′H-spiro[indole-2,1′-indolizin]-7′-yl]-3-methoxyprop-2-enoate
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C23H30N2O5
Molar mass 414.502 g·mol−1
3D model (JSmol)
  • CC[C@H](C1)[C@](/C(C(OC)=O)=C\OC)([H])C[C@@](N1CC2)([H])[C@]32NC4=CC=CC(OC)=C4C3=O
  • InChI=1S/C23H30N2O5/c1-5-14-12-25-10-9-23(19(25)11-15(14)16(13-28-2)22(27)30-4)21(26)20-17(24-23)7-6-8-18(20)29-3/h6-8,13-15,19,24H,5,9-12H2,1-4H3/b16-13+/t14-,15+,19+,23+/m1/s1
  • Key:BAEJBRCYKACTAA-WGUOAFTMSA-N

Mitragynine pseudoindoxyl is a rearrangement product of 7-hydroxymitragynine, an active metabolite of mitragynine. [1]

Contents

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

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]

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. ↑ 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. PMID   3419199.
  2. 1 2 Kamble SH, León F, King TI, Berthold EC, Lopera-Londoño C, Siva Rama Raju K, et al. (December 2020). "Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy". ACS Pharmacology & Translational Science. 3 (6): 1063–1068. doi:10.1021/acsptsci.0c00075. PMC   7737207 . PMID   33344889.
  3. 1 2 3 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. doi:10.1038/s41589-022-01208-y. PMC   11098091 . PMID   36411392. S2CID   245021836.
  4. 1 2 3 4 5 Váradi A, Marrone GF, Palmer TC, Narayan A, Szabó MR, Le Rouzic V, et al. (September 2016). "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. doi:10.1021/acs.jmedchem.6b00748. PMC   5344672 . PMID   27556704.
  5. ↑ Gillis A, Kliewer A, Kelly E, Henderson G, Christie MJ, Schulz S, et al. (December 2020). "Critical Assessment of G Protein-Biased Agonism at the μ-Opioid Receptor". Trends in Pharmacological Sciences. 41 (12): 947–959. doi:10.1016/j.tips.2020.09.009. hdl: 1983/4b7637f4-981f-440e-be41-82e7dd153458 . PMID   33097283.
  6. ↑ Spetea M, Schmidhammer H (June 2019). "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. doi:10.1021/acscentsci.9b00462. PMC   6598155 . PMID   31263752.
  7. ↑ Kamble SH, León F, King TI, Berthold EC, Lopera-Londoño C, Siva Rama Raju K, et al. (December 2020). "Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy". ACS Pharmacology & Translational Science. 3 (6): 1063–1068. doi:10.1021/acsptsci.0c00075. PMC   7737207 . PMID   33344889.
  8. ↑ Chakraborty S, Uprety R, Slocum ST, Irie T, Le Rouzic V, Li X, et al. (November 2021). "Oxidative Metabolism as a Modulator of Kratom's Biological Actions". Journal of Medicinal Chemistry. 64 (22): 16553–16572. doi:10.1021/acs.jmedchem.1c01111. PMC   8673317 . PMID   34783240.
  9. ↑ 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. PMID   11960505.
  10. ↑ 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. PMID   10428019.
  11. ↑ Kim J, Schneekloth JS, Sorensen EJ (September 2012). "A chemical synthesis of 11-methoxy mitragynine pseudoindoxyl featuring the interrupted Ugi reaction". Chemical Science. 3 (9): 2849–2852. doi:10.1039/C2SC20669B. PMC   3714104 . PMID   23878716.
  12. ↑ Angyal P, Hegedüs K, Mészáros BB, Daru J, Dudás Á, Galambos AR, et al. (2023-02-02). "Syntheses and structural plasticity of kratom pseudoindoxyl metabolites". ChemRxiv. doi: 10.26434/chemrxiv-2023-62vzz-v2 .
  13. ↑ Angyal P, Hegedüs K, Mészáros BB, Daru J, Dudás Á, Galambos AR, et al. (August 2023). "Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl Metabolites". Angewandte Chemie. 62 (35) e202303700. Bibcode:2023ACIE...62E3700A. doi: 10.1002/anie.202303700 . PMID   37332089.
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