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

Matsumoto, Kenjiro; Takayama, Hiromitsu; Narita, Minoru; Nakamura, Atsushi; Suzuki, Masami; Suzuki, Tsutomu; Murayama, Toshihiko; Wongseripipatana, Sumphan; Misawa, Kaori; Kitajima, Mariko; Tashima, Kimihito; Horie, Syunji

doi:10.1016/j.neuropharm.2008.05.003

Cited by 45 publications

(54 citation statements)

References 30 publications

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“…Among those derivatives, the C10-fluorinated derivative, MGM-9, showed the highest potency (Takayama et al, 2006). MGM-16, the C10-fluorinated derivative of MGM-15, showed the most potent opioid agonistic effects among the derivatives tested previously (Takayama et al, 2002(Takayama et al, , 2006Matsumoto et al, 2008). MGM-16 showed full agonistic properties on m-and d-opioid receptors.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously synthesized opioid analgesics from the indole alkaloid mitragynine (Takayama et al, 2002(Takayama et al, , 2006Matsumoto et al, 2004Matsumoto et al, , 2008Takayama, 2004). We have surveyed these compounds for their opioid agonistic activities in vitro to elucidate the specific structure necessary for its pharmacophore to bind to opioid receptors.…”

Section: Discussionmentioning

confidence: 99%

“…d-Opioid receptor activation leads to decreased chronic pain but weakly influences acute pain, in contrast to m-opioid receptor activation (Gaveriaux-Ruff et al, 2011). A novel strategy for pain management is to use dualacting and/or mixed opioid agonists (Matsumoto et al, 2008;Cremeans et al, 2012). Therefore, opioid agonists, which act on not only d-but also m-opioid receptor subtypes, might be broadspectrum analgesics useful to treat a variety of painful conditions.…”

Section: Introductionmentioning

confidence: 99%

“…We have reported that 7-hydroxymitragynine induces a potent antinociceptive effect on mouse acute pain through the activation of m-opioid receptors. It is approximately 14 times more potent than morphine when orally administered (Matsumoto et al, 2008). Furthermore, 7-hydroxymitragynine inhibited gastrointestinal transit (GIT) less potently than morphine at each equally antinociceptive dose in mice (Matsumoto et al, 2006a).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, we developed novel opioid analgesics derived from 7-hydroxymitragynine that have different pharmacophore groups from morphine that bind to m-opioid receptors. We found a novel dual-acting m-and k-opioid agonist, (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 (MGM-9), which has stronger antinociceptive and weaker rewarding effects than morphine (Matsumoto et al, 2008). 7-Hydroxymitragynine-related indole alkaloids have interesting pharmacological characteristics such as high oral potency and few side effects.…”

Section: Introductionmentioning

confidence: 99%

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Orally Active Opioid μ/δ Dual Agonist MGM-16, a Derivative of the Indole Alkaloid Mitragynine, Exhibits Potent Antiallodynic Effect on Neuropathic Pain in Mice

Matsumoto

Narita

Muramatsu

et al. 2013

J Pharmacol Exp Ther

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(E)-Methyl 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-methoxyacrylate (7-hydroxymitragynine), a main active constituent of the traditional herbal medicine Mitragyna speciosa, is an indole alkaloid that is structurally different from morphine. 7-Hydroxymitragynine induces a potent antinociceptive effect on mouse acute pain through m-opioid receptors. In this study, we developed dual-acting m-and d-opioid agonists MGM-15 and MGM-16 from 7-hydroxymitragynine for the treatment of acute and chronic pain. MGM-16 showed a higher potency than that of 7-hydroxymitragynine and MGM-15 in in vitro and in vivo assays. MGM-16 exhibited a high affinity for m-and d-opioid receptors, with K i values of 2.1 and 7.0 nM, respectively. MGM-16 showed m-and d-opioid full agonistic effects in a guanosine 59-O-(3-[ 35 S]thiotriphosphate) binding assay and in a functional test using electrically elicited guinea pig ileum and mouse vas deferens contractions. Systemic administration of MGM-16 produced antinociceptive effects in a mouse acute pain model and antiallodynic effects in a chronic pain model. The antinociceptive effect of MGM-16 was approximately 240 times more potent than that of morphine in a mouse tail-flick test, and its antiallodynic effect was approximately 100 times more potent than that of gabapentin in partial sciatic nerve-ligated mice, especially with oral administration. The antinociceptive effect of MGM-16 was completely and partially blocked by the m-selective antagonist b-funaltrexamine hydrochloride (b-FNA) and by the d-selective antagonist naltrindole, respectively, in a tail-flick test. The antiallodynic effect of MGM-16 was completely blocked by b-FNA and naltrindole in a neuropathic pain model. These findings suggest that MGM-16 could become a class of a compound with potential therapeutic utility for treating neuropathic pain.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Orally Active Opioid μ/δ Dual Agonist MGM-16, a Derivative of the Indole Alkaloid Mitragynine, Exhibits Potent Antiallodynic Effect on Neuropathic Pain in Mice

Matsumoto

Narita

Muramatsu

et al. 2013

J Pharmacol Exp Ther

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Development and validation of a UPLC‐MS/MS method for the determination of 7‐hydroxymitragynine, a μ‐opioid agonist, in rat plasma and its application to a pharmacokinetic study

Vuppala

Jamalapuram

Furr

et al. 2013

Biomedical Chromatography

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A simple, sensitive and specific ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed and validated to determine the concentrations of 7-hydroxymitragynine in rat plasma. Following a single step liquid-liquid extraction of plasma samples using chloroform, 7-hydroxymitragynine and the internal standard (tryptoline) were separated on an Acquity UPLC™ BEH C18 (1.7 μm, 2.1 mm×50 mm) column using an isocratic elution at a flow rate of 0.2 mL/min. The mobile phase consisted of 0.1% acetic acid in water and 0.1% acetic acid in acetonitrile (10:90, v/v). The run was 2.5 min. The analysis was carried out under the multiple reaction-monitoring mode using positive electrospray ionization. Protonated ions [M+H]+ and their respective product ions were monitored at the following transitions: 415>190 for 7-hydroxymitragynine and 173>144 for the internal standard. The calibration curve was linear over the range of 10 to 4000 ng/mL (r2=0.999) with a lower limit of quantification (LLOQ) of 10 ng/mL. The extraction recoveries ranged from 62.0% to 67.3% at concentrations (20, 600, 3200 ng/mL). Intra- and inter-day assay precisions (relative standard deviation) were less than 15% and the accuracy was within 96.5% to 104.0%. This validated method was successfully applied to quantify 7-hydroxymitragynine in rat plasma following intravenous administration.

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A systematic review of (pre)clinical studies on the therapeutic potential and safety profile of kratom in humans

Prevete

Kuypers

Theunissen

et al. 2021

Human Psychopharmacology

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Introduction: Kratom (Mitragyna speciosa) is a tropical plant traditionally used as an ethnomedicinal remedy for several conditions in South East Asia. Despite the increased interest in its therapeutical benefits in Western countries, little scientific evidence is available to support such claims, and existing data remain limited to kratom's chronic consumption.Objective: Our study aims to investigate (pre)clinical evidence on the efficacy of kratom as a therapeutic aid and its safety profile in humans. Methods: A systematic literature search using PubMed and the Medline database was conducted between April and November 2020. Results: Both preclinical (N = 57) and clinical (N = 18) studies emerged from our search. Preclinical data indicated a therapeutic value in terms of acute/chronic pain (N = 23), morphine/ethanol withdrawal, and dependence (N = 14), among other medical conditions (N = 26). Clinical data included interventional studies (N = 2) reporting reduced pain sensitivity, and observational studies (N = 9) describing the association between kratom's chronic (daily/frequent) use and safety issues, in terms of health consequences (e.g., learning impairment, high cholesterol level, dependence/withdrawal).Conclusions: Although the initial (pre)clinical evidence on kratom's therapeutic potential and its safety profile in humans is encouraging, further validation in large, controlled clinical trials is required.

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Cited by 45 publications

References 30 publications

Orally Active Opioid μ/δ Dual Agonist MGM-16, a Derivative of the Indole Alkaloid Mitragynine, Exhibits Potent Antiallodynic Effect on Neuropathic Pain in Mice

Orally Active Opioid μ/δ Dual Agonist MGM-16, a Derivative of the Indole Alkaloid Mitragynine, Exhibits Potent Antiallodynic Effect on Neuropathic Pain in Mice

Development and validation of a UPLC‐MS/MS method for the determination of 7‐hydroxymitragynine, a μ‐opioid agonist, in rat plasma and its application to a pharmacokinetic study

A systematic review of (pre)clinical studies on the therapeutic potential and safety profile of kratom in humans

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