:Mitragynine pseudoindoxyl
{{Short description|Opioid analgesic compound}}
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{{Infobox drug
| drug_name = Mitragynine pseudoindoxyl
| image = mitragynine-pseudoindoxyl.svg
| image2 = Mitragynine pseudoindoxyl.png
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| CAS_number = 2035457-43-1
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| PubChem = 44301701
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| ChemSpiderID = 23152339
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = BKA67VHE3B
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| ChEMBL = 58362
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| synonyms = {{small|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)-}}
| IUPAC_name = 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
| C=23 | H=30 | N=2 | O=5
| SMILES = CC[C@H](C1)[C@](/C(C(OC)=O)=C\OC)([H])C[C@@](N1CC2)([H])[C@]32NC4=CC=CC(OC)=C4C3=O
| StdInChI = 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
| StdInChIKey = BAEJBRCYKACTAA-WGUOAFTMSA-N
}}
Mitragynine pseudoindoxyl is a rearrangement product of 7-hydroxymitragynine, an active metabolite of mitragynine.{{cite journal | vauthors = Jansen KL, Prast CJ | title = Ethnopharmacology of kratom and the Mitragyna alkaloids | journal = Journal of Ethnopharmacology | volume = 23 | issue = 1 | pages = 115–119 | year = 1988 | pmid = 3419199 | doi = 10.1016/0378-8741(88)90121-3 }}
Mitragynine pseudoindoxyl can be produced in the blood as a metabolite of 7-hydroxymitragynine.{{cite journal | vauthors = Kamble SH, León F, King TI, Berthold EC, Lopera-Londoño C, Siva Rama Raju K, Hampson AJ, Sharma A, Avery BA, McMahon LR, McCurdy CR | title = Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy | journal = ACS Pharmacology & Translational Science | volume = 3 | issue = 6 | pages = 1063–1068 | date = December 2020 | pmid = 33344889 | pmc = 7737207 | doi = 10.1021/acsptsci.0c00075 }}
Pharmacology
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.{{cite journal | vauthors = 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 | title = Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2 | journal = Journal of Medicinal Chemistry | volume = 59 | issue = 18 | pages = 8381–8397 | date = September 2016 | pmid = 27556704 | pmc = 5344672 | doi = 10.1021/acs.jmedchem.6b00748 }} 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.{{cite journal | vauthors = Qu Q, Huang W, Aydin D, Paggi JM, Seven AB, Wang H, Chakraborty S, Che T, DiBerto JF, Robertson MJ, Inoue A, Suomivuori CM, Roth BL, Majumdar S, Dror RO, Kobilka BK, Skiniotis G | title = Insights into distinct signaling profiles of the µOR activated by diverse agonists | journal = Nature Chemical Biology | volume = 19 | issue = 4 | pages = 423–430 | date = April 2023 | pmid = 36411392 | doi = 10.1038/s41589-022-01208-y | s2cid = 245021836 | pmc = 11098091 }} 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.{{cite journal | vauthors = Spetea M, Schmidhammer H | title = Unveiling 7-Hydroxymitragynine as the Key Active Metabolite of Mitragynine and the Promise for Creating Novel Pain Relievers | journal = ACS Central Science | volume = 5 | issue = 6 | pages = 936–938 | date = June 2019 | pmid = 31263752 | pmc = 6598155 | doi = 10.1021/acscentsci.9b00462 }}{{cite journal | vauthors = Kamble SH, León F, King TI, Berthold EC, Lopera-Londoño C, Siva Rama Raju K, Hampson AJ, Sharma A, Avery BA, McMahon LR, McCurdy CR | title = Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy | journal = ACS Pharmacology & Translational Science | volume = 3 | issue = 6 | pages = 1063–1068 | date = December 2020 | pmid = 33344889 | pmc = 7737207 | doi = 10.1021/acsptsci.0c00075 }}{{cite journal | vauthors = Chakraborty S, Uprety R, Slocum ST, Irie T, Le Rouzic V, Li X, Wilson LL, Scouller B, Alder AF, Kruegel AC, Ansonoff M, Varadi A, Eans SO, Hunkele A, Allaoa A, Kalra S, Xu J, Pan YX, Pintar J, Kivell BM, Pasternak GW, Cameron MD, McLaughlin JP, Sames D, Majumdar S | title = Oxidative Metabolism as a Modulator of Kratom's Biological Actions | journal = Journal of Medicinal Chemistry | volume = 64 | issue = 22 | pages = 16553–16572 | date = November 2021 | pmid = 34783240 | pmc = 8673317 | doi = 10.1021/acs.jmedchem.1c01111 }}
Chemistry
Mitragynine pseudoindoxyl was first accessible via biomimetic semisynthesis from mitragynine.{{cite journal | vauthors = 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 | title = Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands | journal = Journal of Medicinal Chemistry | volume = 45 | issue = 9 | pages = 1949–1956 | date = April 2002 | pmid = 11960505 | doi = 10.1021/jm010576e }}{{cite journal | vauthors = Yamamoto LT, Horie S, Takayama H, Aimi N, Sakai S, Yano S, Shan J, Pang PK, Ponglux D, Watanabe K | title = Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa | journal = General Pharmacology | volume = 33 | issue = 1 | pages = 73–81 | date = July 1999 | pmid = 10428019 | doi = 10.1016/S0306-3623(98)00265-1 }} Total synthesis of an unnatural analogue was reported featuring an interrupted Ugi reaction as the key step.{{cite journal | vauthors = Kim J, Schneekloth JS, Sorensen EJ | title = A chemical synthesis of 11-methoxy mitragynine pseudoindoxyl featuring the interrupted Ugi reaction | journal = Chemical Science | volume = 3 | issue = 9 | pages = 2849–2852 | date = September 2012 | pmid = 23878716 | pmc = 3714104 | doi = 10.1039/C2SC20669B }} Scalable and modular total synthesis of the natural product has also been accomplished using a chiral pool based strategy.{{Cite journal | vauthors = Angyal P, Hegedüs K, Mészáros BB, Daru J, Dudás Á, Galambos AR, Essmat N, Al-Khrasani M, Varga S, Soós T |date=2023-02-02 |title=Syntheses and structural plasticity of kratom pseudoindoxyl metabolites | journal = ChemRxiv |url=https://chemrxiv.org/engage/chemrxiv/article-details/63dab15989c04b6693c92cba |language=en |doi=10.26434/chemrxiv-2023-62vzz-v2}}{{cite journal | vauthors = Angyal P, Hegedüs K, Mészáros BB, Daru J, Dudás Á, Galambos AR, Essmat N, Al-Khrasani M, Varga S, Soós T | title = Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl Metabolites | journal = Angewandte Chemie | pages = e202303700 | date = June 2023 | volume = 62 | issue = 35 | pmid = 37332089 | doi = 10.1002/anie.202303700 | doi-access = free }} This study also demonstrated structural plasticity in biological systems.