7-Hydroxymitragynine

7-Hydroxymitragynine
Clinical data
Other names	7α-Hydroxy-7H-mitragynine; 9-Methoxycorynantheidine hydroxyindolenine
Routes of; administration	By mouth; inhalation
Drug class	Opioid
ATC code	None;
Legal status
Legal status	BR: Class F1 (Prohibited narcotics); US: Unscheduled;
Pharmacokinetic data
Metabolites	Mitragynine pseudoindoxyl
Identifiers
	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;
CAS Number	174418-82-7 ;
PubChem CID	44301524;
ChemSpider	23152144 ;
UNII	2T3TWA75R0;
ChEMBL	ChEMBL61630 ;
CompTox Dashboard (EPA)	DTXSID20903988 ;
Chemical and physical data
Formula	C23H30N2O5
Molar mass	414.502 g·mol−1
3D model (JSmol)	Interactive image; Interactive image;
	SMILES 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 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 ; Key:RYENLSMHLCNXJT-CYXFISRXSA-N ;

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 mitragynine present in the Mitragyna speciosa. 7-OH binds to opioid receptors like mitragynine, but research suggests that 7-OH binds with greater efficacy.^[4]

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.^[5]

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.^[6]^[7] 7-OH does not appear to activate the β-arrestin pathway, distinguishing it from traditional opiate & opioid chemicals.^[6] It shares this trait with mitragynine.

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.^[8]

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.^[9]

Another study found the binding affinity of 7-OH-MIT to be MOR 13.5nM and DOR 155nM and KOR 123nM ^[10]

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 leave 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

^ ^a ^b Chemical Abstracts Service: Columbus, OH, 2004; RN 174418-82-7 (accessed via SciFinder Scholar, version 2007.3; November 30, 2011)
^ 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.
^ 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. Bibcode:1994PlMed..60..580P. doi:10.1055/s-2006-959578. PMID 17236085. S2CID 260252538.
^ 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.
^ Smith KE, Boyer EW, Grundmann O, McCurdy CR, Sharma A (2024). "The rise of novel, semi-synthetic 7-hydroxymitragnine products". Addiction. 120 (2): 387–388. doi:10.1111/add.16728. PMID 39627873.
^ ^a ^b 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.
^ 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.
^ 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 (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.
^ 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 (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.
^ 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 (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.

[CAS-1] Chemical Abstracts Service: Columbus, OH, 2004; RN 174418-82-7 (accessed via SciFinder Scholar, version 2007.3; November 30, 2011)

[Matsumoto_K,_Horie_S,_Ishikawa_H,_et_al._2004_2143–55-2] 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. Bibcode:1994PlMed..60..580P. 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. 120 (2): 387–388. doi:10.1111/add.16728. PMID 39627873.

[Eastlack_Cornett_Kaye_2020-6] 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.

[:0-7] 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.

[8] 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 (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.

[9] 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 (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.

[10] 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 (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.

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7-Hydroxymitragynine

Pharmacology

Synthesis

References

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