Mitragynine

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Mitragynine
Mitragynine2DACS.svg
Mitragynine2cropped.png
Names
IUPAC name
Methyl (2E)-2-[(2S,4S,5S)-5-ethyl-12-methoxy-7,17-diazatetracyclo[8.7.0.02,7.011,16]heptadeca-1(10),11(16),12,14-tetraen-4-yl]-3-methoxyprop-2-enoate
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
KEGG
UNII
Properties
C23H30N2O4
Molar mass 398.4953 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Mitragynine is an indole-based opioid-receptor agonist and the most abundant active alkaloid in the plant Mitragyna speciosa, commonly known as kratom[1] and biak-biak.[2] Dry kratom leaf contains roughly 1.2–2.1% mitragynine.[3]

Pharmacology[edit]

Mitragynine itself acts primarily via μ-opioid receptors, though its oxidation product mitragynine pseudoindoxyl, acts as a selective μ-opioid agonist but with less affinity for δ or κ receptors.[4][5] Another alkaloid with a major contribution to the μ-opioid activity of the kratom plant is the related compound 7-hydroxymitragynine, which, while present in the plant in much smaller quantities than mitragynine, is a much more potent μ-opioid partial agonist.[6] In murine models, the extracted alkaloids of the Kratom plant are shown to cause an insignificant amount of drug induced respiratory depression, unlike full μ-opioid agonists.[7]

Derivatives[edit]

Research on mitragynine structure–activity relationships have led to discovery of new potent opioid agonists, notably some C10-halogen and 2,3-ethylene glycol bridged derivatives of 7-hydroxymitragynine. The most potent one is the 10-fluoro ethylene glycol adduct of 7-hydroxymitragynine with a potency 4-fold higher than 7-hydroxymitragynine.[citation needed] Other modification led to 2,3-dihydro derivatives such as MGM-15, prepared by reduction of 7-hydroxymitragynine with sodium borohydride. The antinociceptive effect of MGM-15 is between 15 and 50 times more potent than that of morphine after subcutaneous and oral administration.[8]


Pharmacokinetics[edit]

Mitragynine has been studied in chronic users. It undergoes extensive hepatic metabolism with linear kinetics and long half life.[9]

Detection in body fluids[edit]

Blood mitragynine concentrations are expected to be in a range of 10–50 μg/L in persons using the drug recreationally. Detection in body fluids is typically by liquid chromatography-mass spectrometry.[10][11]

Structure[edit]

It is structurally related to yohimbine but shows a totally different pharmacology.

Synthesis[edit]

The first total synthesis of mitragynine was reported by Takayama et al. in 1995.[12]

See also[edit]

References[edit]

  1. ^ Jansen KL, Prast CJ (1988). "Ethnopharmacology of kratom and the Mitragyna alkaloids". J Ethnopharmacol. 23 (1): 115–19. doi:10.1016/0378-8741(88)90121-3. PMID 3419199.
  2. ^ Raffa, RB; Beckett, JR; Brahmbhatt, VN; et al. (2013). "Orally active opioid compounds from a non-poppy source". J Med Chem. 56 (12): 4840–48. doi:10.1021/jm400143z. PMID 23517479.
  3. ^ Kikura-Hanajiri, Ruri; Kawamura, Maiko; Maruyama, Takuro; Kitajima, Mariko; Takayama, Hiromitsu; Goda, Yukihiro (July 2009). "Simultaneous analysis of mitragynine, 7-hydroxymitragynine, and other alkaloids in the psychotropic plant "kratom" (Mitragyna speciosa) by LC-ESI-MS". Forensic Toxicology. 27 (2): 67–74. doi:10.1007/s11419-009-0070-5. ISSN 1860-8973.
  4. ^ 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 (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". J. Med. Chem. 45 (9): 1949–56. doi:10.1021/jm010576e. PMID 11960505.
  5. ^ Yamamoto, Leonardo T.; Horie, Syunji; Takayama, Hiromitsu; Aimi, Norio; Sakai, Shin-ichiro; Yano, Shingo; Shan, Jie; Pang, Peter K. T.; Ponglux, Dhavadee; Watanabe, Kazuo (July 1999). "Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa". General Pharmacology: The Vascular System. 33 (1): 73–81. doi:10.1016/S0306-3623(98)00265-1. PMID 10428019.
  6. ^ Kruegel, AC; Gassaway, MM; Kapoor, A; Váradi, A; Majumdar, S; Filizola, M; Javitch, JA; Sames, D (2016). "Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators". J. Am. Chem. Soc. 138 (21): 6754–64. doi:10.1021/jacs.6b00360. PMC 5189718. PMID 27192616.
  7. ^ 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 (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): 8381–97. doi:10.1021/acs.jmedchem.6b00748. PMC 5344672. PMID 27556704. Archived from the original on 6 May 2018.
  8. ^ Robert B. Raffa - Kratom and Other Mitragynines: The Chemistry and Pharmacology of Opioids from a Non-Opium Source - October 29, 2014 by CRC Press - ISBN 9781482225181
  9. ^ Trakulsrichai, Satariya; Sathirakul, Korbtham; Auparakkitanon, Saranya; Krongvorakul, Jatupon; Sueajai, Jetjamnong; Noumjad, Nantida; Sukasem, Chonlaphat; Wananukul, Winai (2015-04-29). "Pharmacokinetics of mitragynine in man". Drug Design, Development and Therapy. 9: 2421–29. doi:10.2147/DDDT.S79658. ISSN 1177-8881. PMC 4425236. PMID 25995615.
  10. ^ Le, David; Goggin, Melissa M.; Janis, Gregory C. (November–December 2012). "Analysis of Mitragynine and Metabolites in Human Urine for Detecting the Use of the Psychoactive Plant Kratom". Journal of Analytical Toxicology. 36 (9): 616–25. doi:10.1093/jat/bks073. ISSN 1945-2403. PMID 23024321.
  11. ^ Baselt RC (2014). Disposition of toxic drugs and chemicals in man. Seal Beach, Calif.: Biomedical Publications. p. 1382. ISBN 978-0-9626523-9-4.
  12. ^ Takayama H.; Maeda M.; Ohbayashi S.; Kitajima M.; Sakai S.-i.; Aimi N. (1995). "The First Total Synthesis of (−)-Mitragynine, An Analgesic Indole Alkaloid in Mitragyna speciosa". Tetrahedron Letters. 36 (51): 9337–40. doi:10.1016/0040-4039(95)02022-H.

External links[edit]