7-Hydroxymitragynine

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 natural product derived from mitragynine present in the kratom leaf. 7-OH binds to opioid receptors like mitragynine, but research suggests that 7-OH binds with greater efficacy.^[4]

7-Hydroxymitragynine

Clinical data
Other names	7α-Hydroxy-7H-mitragynine;[1] 9-Methoxycorynantheidine hydroxyindolenine[1]
Routes of administration	By mouth
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 N
PubChem CID	44301524
ChemSpider	23152144 Y
UNII	2T3TWA75R0
ChEMBL	ChEMBL61630 Y
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 Y Key:RYENLSMHLCNXJT-CYXFISRXSA-N Y

Dependence and withdrawal

Main article: Mitragynine § Dependence and withdrawal

Pharmacology

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.^[5][6] 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.^[5]

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.^[5]

Metabolism

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.^[7] 7-Hydroxymitragynine can metabolize to mitragynine pseudoindoxyl in the blood but not in the liver.^[8][9] Interestingly, this even more potent opioid was revealed to exist in a mixture of stereoisomers in biological systems.^[9]

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	[10]
Mitragynine	7.24	60.3	1,100	1:8:152	[10]
Mitragynine pseudoindoxyl	0.087	3.02	79.4	1:35:913	[10]

See also

• Ajmalicine
• Mitragynine
• Mitragynine pseudoindoxyl
• Mitraphylline
• β-Prodine - molecule overlaying 7-hydroxymitragynine's opioid QSAR (Quantitative structure-activity relationship)

References

1. 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. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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

• Takayama H (August 2004). "Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa". Chemical & Pharmaceutical Bulletin. 52 (8): 916–928. doi:10.1248/cpb.52.916. PMID 15304982.