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7-Hydroxymitragynine

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7-Hydroxymitragynine
Clinical data
Other names7α-Hydroxy-7H-mitragynine;[1] 9-Methoxycorynantheidine hydroxyindolenine[1]
Routes of
administration		By mouth
Drug classOpioid
ATC code
  • None
Legal status
Legal status
  • BR: Class F1 (Prohibited narcotics)
  • US: Unscheduled
Pharmacokinetic data
MetabolitesMitragynine pseudoindoxyl
Identifiers
  • 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
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC23H30N2O5
Molar mass414.502 g·mol−1
3D model (JSmol)
  • CC[C@@H]1CN2CC[C@@]3(O)C(=Nc4cccc(OC)c34)[C@@H]2C[C@@H]1\C(=C/OC)C(=O)OC

  • 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
  • InChI=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 checkY
  • Key:RYENLSMHLCNXJT-CYXFISRXSA-N checkY

7-Hydroxymitragynine (7-OH) is a terpenoid indole alkaloid from the plant Mitragyna speciosa, commonly known as kratom.[2] It was first described in 1994[3] and is a human metabolite metabolized from mitragyna speciosa present in the kratom leaf. 7-OH binds to opioid receptors like mitragynine, but research suggests that 7-OH binds with greater efficacy.[4]

Adverse effects

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7-Hydroxymitragynine (7-OH), a metabolite of the psychoactive botanical Mitragyna speciosa (commonly known as kratom), exhibits significantly higher binding affinity to mu-opioid receptors (MOR) than morphine, with estimates ranging from 14 to 22 times greater potency. 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.[5]

Recent developments in the market have introduced semi-synthetic 7-OH products, which differ from traditional kratom preparations in both concentration and route of administration. These novel products often contain up to 98% 7-OH and are marketed in formulations such as sublingual tablets and nasal sprays. Some of these formulations bypass first-pass metabolism, significantly increasing bioavailability and potentially amplifying their opioid-like effects.[6]

Pharmacology

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7-Hydroxymitragynine, like mitragynine, appears to be a mixed opioid receptor agonist/antagonist, acting as a partial agonist at μ-opioid receptors and as a competitive antagonist at δ- and κ-opioid receptors.[7][8] Evidence suggests that 7-OH is more potent than both mitragynine and morphine. 7-OH does not activate the β-arrestin pathway like traditional opioids, meaning symptoms such as respiratory depression, constipation, and sedation are much less pronounced.[7]

7-OH is generated from mitragynine in vivo by hepatic metabolism and may account for a significant portion of the effects traditionally associated with mitragynine. Although 7-OH occurs naturally in kratom leaves, it does so in such low amounts that any ingested 7-OH is inconsequential compared to the 7-OH generated in the body.[7]

Metabolism

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7-Hydroxymitragynine can convert into mitragynine up to 45% in human liver microsomes over a two-hour incubation and was degraded up to 27% in simulated gastric fluid and degraded up to 6% in simulated intestinal fluid.[9] 7-Hydroxymitragynine can metabolize to mitragynine pseudoindoxyl in the blood but not in the liver.[10][11] Interestingly, this even more potent opioid was revealed to exist in a mixture of stereoisomers in biological systems.[11]

Mitragynine Pseudoindoxyl
Mitragyna speciosa alkaloids at opioid receptors
Compound Affinities (KiTooltip Inhibitor constant) Ratio Ref
MORTooltip μ-Opioid receptor DORTooltip δ-Opioid receptor KORTooltip κ-Opioid receptor MOR:DOR:KOR
7-Hydroxymitragynine 13.5 155 123 1:11:9 [12]
Mitragynine 7.24 60.3 1,100 1:8:152 [12]
Mitragynine pseudoindoxyl 0.087 3.02 79.4 1:35:913 [12]

See also

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References

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  1. ^ a b Chemical Abstracts Service: Columbus, OH, 2004; RN 174418-82-7 (accessed via SciFinder Scholar, version 2007.3; November 30, 2011)
  2. ^ Matsumoto K, Horie S, Ishikawa H, Takayama H, Aimi N, Ponglux D, Watanabe K (March 2004). "Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa". Life Sciences. 74 (17): 2143–2155. doi:10.1016/j.lfs.2003.09.054. PMID 14969718.
  3. ^ Ponglux D, Wongseripipatana S, Takayama H, Kikuchi M, Kurihara M, Kitajima M, et al. (December 1994). "A New Indole Alkaloid, 7 alpha-Hydroxy-7H-mitragynine, from Mitragyna speciosa in Thailand". Planta Medica. 60 (6): 580–581. doi:10.1055/s-2006-959578. PMID 17236085. S2CID 260252538.
  4. ^ Kruegel AC, Grundmann O (May 2018). "The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse". Neuropharmacology. 134 (Pt A): 108–120. doi:10.1016/j.neuropharm.2017.08.026. PMID 28830758. S2CID 24009429.
  5. ^ Smith KE, Boyer EW, Grundmann O, McCurdy CR, Sharma A (2024). "The rise of novel, semi-synthetic 7-hydroxymitragnine products". Addiction. doi:10.1111/add.16728. PMID 39627873.
  6. ^ Smith KE, Boyer EW, Grundmann O, McCurdy CR, Sharma A (2024). "The rise of novel, semi-synthetic 7-hydroxymitragnine products". Addiction. doi:10.1111/add.16728. PMID 39627873.
  7. ^ a b c Eastlack SC, Cornett EM, Kaye AD (June 2020). "Kratom-Pharmacology, Clinical Implications, and Outlook: A Comprehensive Review". Pain and Therapy. 9 (1): 55–69. doi:10.1007/s40122-020-00151-x. PMC 7203303. PMID 31994019.
  8. ^ Chang-Chien GC, Odonkor CA, Amorapanth P (2017). "Is Kratom the New 'Legal High' on the Block?: The Case of an Emerging Opioid Receptor Agonist with Substance Abuse Potential". Pain Physician. 20 (1): E195–E198. doi:10.36076/ppj.2017.1.E195. PMID 28072812.
  9. ^ Manda V, Avula B, Ali Z, Khan I, Walker L, Khan S (2014). "Evaluation of in Vitro Absorption, Distribution, Metabolism, and Excretion (ADME) Properties of Mitragynine, 7-Hydroxymitragynine, and Mitraphylline". Planta Medica. 80 (7): 568–576. doi:10.1055/s-0034-1368444. PMID 24841968.
  10. ^ 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.
  11. ^ a b 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.
  12. ^ a b c 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.

Further reading

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