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Mitragynine pseudoindoxyl

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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
  • 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
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC23H30N2O5
Molar mass414.502 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]

Mitragynine pseudoindoxyl can be produced in the blood as a metabolite of 7-hydroxymitragynine.[2]

Pharmacology

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Mitragynine pseudoindoxyl is a μ-opioid receptor agonist and δ-opioid receptor antagonist. It is a G protein biased 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

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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.

See also

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References

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  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. ^ 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. ^ a b 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ Angyal P, Hegedüs K, Mészáros BB, Daru J, Dudás Á, Galambos AR, et al. (June 2023). "Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl Metabolites". Angewandte Chemie. 62 (35): e202303700. doi:10.1002/anie.202303700. PMID 37332089.
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