7-Hydroxymitragynine

7-HMG, 7-OH

7-hydroxymitragynine (7-OH) is a minor alkaloid compound found in the plant Mitragynia speciosa (aka kratom).1 Although it is a minor alkaloid in terms of quantity, 7-OH is very interesting to scientists because of its potency and analgesic effects.

The Chemistry of 7-Hydroxymitragynine

7-OH is the oxidized derivative of mitragynine, the primary alkaloid in kratom.

Studies exploring the total and partial synthesis of 7-OH (and its parent compound mitragynine) reveal some interesting findings regarding the structure-activity relationship (SAR) of their molecular scaffold and its interaction with mu opioid receptors (MOR).2–7 For example, the MOR activity of 7-OH stops when small molecular changes are made to the acrylate and ethyl groups on one of the rings. Also, the demethylation of the aryl methoxy group reduces the potency of 7-OH at the MOR.

The Pharmacology of 7-Hydroxymitragynine

Studies have been done to examine how 7-OH interacts with the human mu opioid receptors (hMORs).4 Combining docking study observations with what is known about the SAR of 7-OH at hMORs, suggests that 7-OH and its structural analogs adopt a distinct binding pose in the receptor pocket. Additional experiments showed that 7-OH had a Ki value of 47 nM and was a partial agonist at hMOR.

In addition, studies have shown that 7-OH acts as a competitive antagonist at the human kappa (hKOR) and delta (hDOR) opioid receptors.4

Data from a 2014 study indicates that 7-OH has sufficient permeability and efflux ratios to pass through the blood-brain barrier via passive diffusion.8

The Applications and Potential of 7-Hydroxymitragynine

Research indicates that the analgesic effects of 7-OH are due to its agonist behavior at hMOR. In mice, 7-OH has a potency at hMOR that is 4- to 5-fold higher than the opioid agonist morphine when administered subcutaneously.9,10 Via the oral route, 7-OH is 10- to 20-fold more potent than morphine (morphine has poor oral bioavailability).11 But because it is only a partial agonist, 7-OH has side effects that are significantly milder than morphine.12

    References
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  2. Ma J, Yin W, Zhou H, Cook JM. Total Synthesis of the Opioid Agonistic Indole Alkaloid Mitragynine and the First Total Syntheses of 9-Methoxygeissoschizol and 9-Methoxy-Nb-methylgeissoschizol. Org Lett. 2007;9(18):3491-3494. doi:10.1021/ol071220l
  3. Kerschgens IP, Claveau E, Wanner MJ, Ingemann S, Maarseveen JH van, Hiemstra H. Total syntheses of mitragynine, paynantheine and speciogynine via an enantioselective thiourea-catalysed Pictet–Spengler reaction. Chem Commun. 2012;48(100):12243-12245. doi:10.1039/C2CC37023A
  4. Kruegel AC, Gassaway MM, Kapoor A, et al. Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators. J Am Chem Soc. 2016;138(21):6754-6764. doi:10.1021/jacs.6b00360
  5. Ma J, Yin W, Zhou H, Liao X, Cook JM. General Approach to the Total Synthesis of 9-Methoxy-Substituted Indole Alkaloids: Synthesis of Mitragynine, as well as 9-Methoxygeissoschizol and 9-Methoxy-Nb-methylgeissoschizol. J Org Chem. 2009;74(1):264-273. doi:10.1021/jo801839t
  6. Takayama H, Ishikawa H, Kurihara M, et al. 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. 2002;45(9):1949-1956. doi:10.1021/jm010576e
  7. Takayama H, Maeda M, Ohbayashi S, Kitajima M, Sakai S, Aimi N. The first total synthesis of (−)-mitragynine, an analgesic indole alkaloid in Mitragyna speciosa. Tetrahedron Letters. 1995;36(51):9337-9340. doi:10.1016/0040-4039(95)02022-H
  8. Manda VK, Avula B, Ali Z, Khan IA, Walker LA, Khan SI. Evaluation of In Vitro Absorption, Distribution, Metabolism, and Excretion (ADME) Properties of Mitragynine, 7-Hydroxymitragynine, and Mitraphylline. Planta Med. 2014;80(07):568-576. doi:10.1055/s-0034-1368444
  9. Matsumoto K, Horie S, Ishikawa H, et al. Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa. Life Sciences. 2004;74(17):2143-2155. doi:10.1016/j.lfs.2003.09.054
  10. Ponglux D, Wongseripipatana S, Takayama H, et al. A new indole alkaloid, 7α-hydroxy-7H-mitragynine from Mitragyna speciosa in Thailand. Planta Medica. 1994;60:580-581.
  11. Matsumoto K, Takayama H, Narita M, et al. MGM-9 [(E)-methyl 2-(3-ethyl-7a,12a-(epoxyethanoxy)-9-fluoro-1,2,3,4,6,7,12,12b-octahydro-8-methoxyindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate], a derivative of the indole alkaloid mitragynine: A novel dual-acting μ- and κ-opioid agonist with potent antinociceptive and weak rewarding effects in mice. Neuropharmacology. 2008;55(2):154-165. doi:10.1016/j.neuropharm.2008.05.003
  12. Matsumoto K, Hatori Y, Murayama T, et al. Involvement of μ-opioid receptors in antinociception and inhibition of gastrointestinal transit induced by 7-hydroxymitragynine, isolated from Thai herbal medicine Mitragyna speciosa. European Journal of Pharmacology. 2006;549(1-3):63-70. doi:10.1016/j.ejphar.2006.08.013