Mitragynine pseudoindoxyl

Mitragynine pseudoindoxyl is a rearrangement product of 7-hydroxymitragynine.[1] It is an analgesic being more potent than morphine.[2][3]

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
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

Pharmacology

Mitragynine pseudoindoxyl is a μ opioid receptor agonist and δ opioid receptor antagonist and acts as a G protein biased agonist at μ opioid receptors and possesses a favourable side effect profile compared to conventional opioids.[4] Cryo-EM structures of μOR-Gi1 complex with mitragynine pseudoindoxyl and lofentanil (one of the most lethal 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.[5] 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 pseuodoindoxyl was first accessible via biomimetic semisynthesis from mitragynine.[2][3][4] Total synthesis of an unnatural analogue was reported featuring an interrupted Ugi reaction as the key step.[9] Scalable and modular total synthesis of the natural product has been also accomplished using a chiral pool based strategy.[10] 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". J Ethnopharmacol. 23 (1): 115–9. doi:10.1016/0378-8741(88)90121-3. PMID 3419199.
  2. Takayama H, Ishikawa H, Kurihara M, Kitajima M, Aimi N, Ponglux D, Koyama F, Matsumoto K, Moriyama T, Yamamoto LT, Watanabe K, Murayama T, Horie S (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". J. Med. Chem. 45 (9): 1949–56. doi:10.1021/jm010576e. PMID 11960505.
  3. Yamamoto, L. T.; Horie, S.; Takayama, H.; Aimi, N.; Sakai, S.; Yano, S.; Shan, J.; Pang, P. K.; Ponglux, D.; Watanabe, K. (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.
  4. Váradi A, Marrone GF, Palmer TC, Narayan A, Szabó MR, Le Rouzic V, Grinnell SG, Subrath JJ, Warner E, Kalra S, Hunkele A, Pagirsky J, Eans SO, Medina JM, Xu J, Pan YX, Borics A, Pasternak GW, McLaughlin JP, Majumdar S (2016). "Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2". J. Med. Chem. 59 (18): 8381–97. doi:10.1021/acs.jmedchem.6b00748. PMC 5344672. PMID 27556704.
  5. Qu, Qianhui; Huang, Weijiao; Aydin, Deniz; Paggi, Joseph M.; Seven, Alpay B.; Wang, Haoqing; Chakraborty, Soumen; Che, Tao; DiBerto, Jeffrey F.; Robertson, Michael J.; Inoue, Asuka; Suomivuori, Carl-Mikael; Roth, Bryan L.; Majumdar, Susruta; Dror, Ron O. (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. ISSN 1552-4469. PMID 36411392. S2CID 245021836.
  6. Spetea, Mariana; Schmidhammer, Helmut (2019-06-26). "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. ISSN 2374-7943. PMC 6598155. PMID 31263752.
  7. Kamble, Shyam H.; León, Francisco; King, Tamara I.; Berthold, Erin C.; Lopera-Londoño, Carolina; Siva Rama Raju, Kanumuri; Hampson, Aidan J.; Sharma, Abhisheak; Avery, Bonnie A.; McMahon, Lance R.; McCurdy, Christopher R. (2020-12-11). "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. ISSN 2575-9108. PMC 7737207. PMID 33344889.
  8. Chakraborty, Soumen; Uprety, Rajendra; Slocum, Samuel T.; Irie, Takeshi; Le Rouzic, Valerie; Li, Xiaohai; Wilson, Lisa L.; Scouller, Brittany; Alder, Amy F.; Kruegel, Andrew C.; Ansonoff, Michael; Varadi, Andras; Eans, Shainnel O.; Hunkele, Amanda; Allaoa, Abdullah (2021-11-25). "Oxidative Metabolism as a Modulator of Kratom's Biological Actions". Journal of Medicinal Chemistry. 64 (22): 16553–16572. doi:10.1021/acs.jmedchem.1c01111. ISSN 0022-2623. PMC 8673317. PMID 34783240.
  9. Kim, Jimin; Schneekloth, John S.; Sorensen, Erik J. (2012-07-30). "A chemical synthesis of 11-methoxy mitragynine pseudoindoxyl featuring the interrupted Ugi reaction". Chemical Science. 3 (9): 2849–2852. doi:10.1039/C2SC20669B. ISSN 2041-6539. PMC 3714104. PMID 23878716.
  10. Angyal, Péter; Hegedüs, Kristóf; Mészáros, Bence Balázs; Daru, János; Dudás, Ádám; Galambos, Anna Rita; Essmat, Nariman; Al-Khrasani, Mahmoud; Varga, Szilárd; Soós, Tibor (2023-02-02). "Syntheses and structural plasticity of kratom pseudoindoxyl metabolites". doi:10.26434/chemrxiv-2023-62vzz-v2. {{cite journal}}: Cite journal requires |journal= (help)
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