7-Hydroxymitragynine
{{Short description|Opioid analgesic compound}}{{Drugbox
| drug_name = 7-Hydroxymitragynine
| IUPAC_name = Methyl (2E)-2-[(2S,3S,7aS,12bS)-3-ethyl-7a-hydroxy-8-methoxy-1,2,3,4,6,7,7a,12b-octahydroindolo[2,3-a]quinolizin-2-yl]-3-methoxyprop-2-enoate
| image = 7-hydroxymitragynine2DACS.svg
| image2 = 7-OH-mitragynine.png
| legal_BR = F1
| legal_US = Unscheduled
| routes_of_administration = By mouth; inhalation
| metabolites = Mitragynine pseudoindoxyl
| CAS_number = 174418-82-7
| CAS_number_Ref = {{cascite|changed|??}}
| ATC_prefix = None
| PubChem = 44301524
| ChemSpiderID = 23152144
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| UNII = 2T3TWA75R0
| UNII_Ref = {{fdacite|changed|FDA}}
| ChEMBL = 61630
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| synonyms = 7α-Hydroxy-7H-mitragynine;Chemical Abstracts Service: Columbus, OH, 2004; RN 174418-82-7 (accessed via SciFinder Scholar, version 2007.3; November 30, 2011)
9-Methoxycorynantheidine hydroxyindolenine
| C = 23
| H = 30
| N = 2
| O = 5
| SMILES = CC[C@@H]1CN2CC[C@@]3(O)C(=Nc4cccc(OC)c34)[C@@H]2C[C@@H]1\C(=C/OC)C(=O)OC
| StdInChI = 1S/C23H30N2O5/c1-5-14-12-25-10-9-23(27)20-17(7-6-8-19(20)29-3)24-21(23)18(25)11-15(14)16(13-28-2)22(26)30-4/h6-8,13-15,18,27H,5,9-12H2,1-4H3/b16-13+/t14-,15+,18+,23+/m1/s1
| StdInChIKey = RYENLSMHLCNXJT-CYXFISRXSA-N
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| class = Opioid
| SMILES2 = CC[C@@H]1CN2CC[C@@]3(O)C(=NC4=CC=CC(OC)=C34)[C@@H]2C[C@@H]1\C(=C/OC)C(=O)OC
}}{{cs1 config|name-list-style=vanc}}
7-Hydroxymitragynine (7-OH) is a terpenoid indole alkaloid from the plant Mitragyna speciosa, commonly known as kratom.{{cite journal | vauthors = Matsumoto K, Horie S, Ishikawa H, Takayama H, Aimi N, Ponglux D, Watanabe K | title = Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa | journal = Life Sciences | volume = 74 | issue = 17 | pages = 2143–2155 | date = March 2004 | pmid = 14969718 | doi = 10.1016/j.lfs.2003.09.054 }} It was first described in 1994{{cite journal | vauthors = Ponglux D, Wongseripipatana S, Takayama H, Kikuchi M, Kurihara M, Kitajima M, Aimi N, Sakai S | display-authors = 6 | title = A New Indole Alkaloid, 7 alpha-Hydroxy-7H-mitragynine, from Mitragyna speciosa in Thailand | journal = Planta Medica | volume = 60 | issue = 6 | pages = 580–581 | date = December 1994 | pmid = 17236085 | doi = 10.1055/s-2006-959578 | bibcode = 1994PlMed..60..580P | s2cid = 260252538 }} and is a human metabolite metabolized from mitragynine present in the Mitragyna speciosa. 7-OH binds to opioid receptors like mitragynine, but research suggests that 7-OH binds with greater efficacy.{{cite journal | vauthors = Kruegel AC, Grundmann O | title = The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse | journal = Neuropharmacology | volume = 134 | issue = Pt A | pages = 108–120 | date = May 2018 | pmid = 28830758 | doi = 10.1016/j.neuropharm.2017.08.026 | s2cid = 24009429 }}
7-Hydroxymitragynine (7-OH), a metabolite of the psychoactive botanical kratom, exhibits significantly higher binding affinity to mu-opioid receptors (MOR) than Mitragynine. Although kratom's primary alkaloid, mitragynine, is associated with lower abuse potential and moderate safety, 7-OH demonstrates opioid-like effects and can substitute for morphine in a dose-dependent manner, raising concerns about its potential for physical dependence and addiction.{{cite journal |url=https://onlinelibrary.wiley.com/doi/10.1111/add.16728?af=R | doi=10.1111/add.16728 | title=The rise of novel, semi-synthetic 7-hydroxymitragnine products | date=2024 | journal=Addiction | pmid=39627873 | vauthors = Smith KE, Boyer EW, Grundmann O, McCurdy CR, Sharma A | volume=120 | issue=2 | pages=387–388 }}
Pharmacology
7-Hydroxymitragynine, like mitragynine, appears to be a mixed opioid receptor agonist/antagonist, with recent research indicating that it acts as a partial agonist at μ-opioid receptors and as a competitive antagonist at δ- and κ-opioid receptors.{{cite journal | vauthors = Eastlack SC, Cornett EM, Kaye AD | title = Kratom-Pharmacology, Clinical Implications, and Outlook: A Comprehensive Review | journal = Pain and Therapy | volume = 9 | issue = 1 | pages = 55–69 | date = June 2020 | pmid = 31994019 | pmc = 7203303 | doi = 10.1007/s40122-020-00151-x }}{{cite journal | vauthors = Chang-Chien GC, Odonkor CA, Amorapanth P | title = Is Kratom the New 'Legal High' on the Block?: The Case of an Emerging Opioid Receptor Agonist with Substance Abuse Potential | journal = Pain Physician | volume = 20 | issue = 1 | pages = E195–E198 | date = 2017 | doi = 10.36076/ppj.2017.1.E195 | pmid = 28072812 | doi-access = free }} 7-OH does not appear to activate the β-arrestin pathway, distinguishing it from traditional opiate & opioid chemicals. It shares this trait with mitragynine.
It has been incorrectly reported that 7-OH-MIT "has binding affinity 14–22 times greater than morphine" in journal published literature titled "The rise of novel, semi-synthetic 7-hydroxymitragynine products". The citation for this claim is another journal published citation titled "Interactive Effects of µ-Opioid and Adrenergic-α2 Receptor Agonists in Rats: Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynine", both studies have the same co-author Christopher R. McCurdy that shows a several times lower binding affinity than Morphine. A notice of correction has not yet been published for this error.{{cite journal | url=https://onlinelibrary.wiley.com/doi/10.1111/add.16728?af=R | doi=10.1111/add.16728 | title=The rise of novel, semi-synthetic 7-hydroxymitragynine products | date=2025 | journal=Addiction | volume=120 | issue=2 | pages=387–388 | pmid=39627873 | vauthors = Smith KE, Boyer EW, Grundmann O, McCurdy CR, Sharma A }}{{cite journal | url=https://jpet.aspetjournals.org/article/S0022-3565(24)00351-3/abstract | pmid=36153006 | doi=10.1124/jpet.122.001192 | title=Interactive Effects of µ-Opioid and Adrenergic-α2 Receptor Agonists in Rats: Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynine | date=2022 | journal=The Journal of Pharmacology and Experimental Therapeutics | volume=383 | issue=3 | pages=182–198 | pmc=9667981 | vauthors = Obeng S, Leon F, Patel A, Zuarth Gonzalez JD, Chaves Da Silva L, Restrepo LF, Gamez-Jimenez LR, Ho NP, Guerrero Calvache MP, Pallares VL, Helmes JA, Shiomitsu SK, Soto PL, Hampson AJ, McCurdy CR, McMahon LR, Wilkerson JL, Hiranita T }}
A study has found the binding affinity of 7-OH-MIT to be μ-opioid receptor (MOR) 37 (± 4) nM and δ-opioid receptor (DOR) 91 (± 8) nM and κ-opioid receptor (KOR) 132 (± 7) nM.{{cite journal | doi=10.1021/acs.jmedchem.6b00748 | title=Mitragynine/Corynantheidine Pseudoindoxyls as Opioid Analgesics with Mu Agonism and Delta Antagonism, Which do Not Recruit β-Arrestin-2 | date=2016 | journal=Journal of Medicinal Chemistry | volume=59 | issue=18 | pages=8381–8397 | pmid=27556704 | pmc=5344672 | 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 Y, Borics A, Pasternak GW, McLaughlin JP, Majumdar S }}
Another study found the binding affinity of 7-OH-MIT to be MOR 16 (± 1) nM and DOR 137 (± 21) nM and KOR 133 (± 37) nM.{{cite journal | url=https://pubs.acs.org/doi/10.1021/jm010576e | doi=10.1021/jm010576e | title=Studies on the Synthesis and Opioid Agonistic Activities of Mitragynine-Related Indole Alkaloids: Discovery of Opioid Agonists Structurally Different from Other Opioid Ligands | date=2002 | journal=Journal of Medicinal Chemistry | volume=45 | issue=9 | pages=1949–1956 | pmid=11960505 | 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 }}
Another study found the binding affinity of 7-OH-MIT to be MOR 13.5nM and DOR 155nM and KOR 123nM {{cite journal | url=https://pubs.acs.org/doi/10.1021/jm010576e | doi=10.1021/jm010576e | title=Studies on the Synthesis and Opioid Agonistic Activities of Mitragynine-Related Indole Alkaloids: Discovery of Opioid Agonists Structurally Different from Other Opioid Ligands | date=2002 | journal=Journal of Medicinal Chemistry | volume=45 | issue=9 | pages=1949–1956 | pmid=11960505 | 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 }}
Synthesis
In natural kratom leaves, 7-Hydroxymitragynine is only present in small amounts from 0.6%-0.7% on average. Therefore, extracting 7-OH in high concentrations directly from natural kratom leaves is not feasible due to the natural yield being too low. This means that all high-concentration 7-OH products must be produced via synthesis. The most common methods usually involve modifying mitragynine, the most abundant alkaloid in kratom, to artificially increase 7-OH concentration via oxidation reactions.
References
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{{Opioid receptor modulators}}
{{DEFAULTSORT:Hydroxymitragynine, 7-}}