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Syunji Horie - One of the best experts on this subject based on the ideXlab platform.
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inhibitory effect of Mitragynine an analgesic alkaloid from thai herbal medicine on neurogenic contraction of the vas deferens
Life Sciences, 2005Co-Authors: Kenjiro Matsumoto, Hiromitsu Takayama, Kazuo Watanabe, Shingo Yano, Syunji Horie, Leonardo T Yamamoto, Dhavadee Ponglux, Jie Shan, Peter K T PangAbstract:Abstract The effect of an indole-alkaloid Mitragynine isolated from the Thai medicinal herb kratom ( Mitragyna speciosa ) on neurogenic contraction of smooth muscle was studied in guinea-pig vas deferens. Mitragynine inhibited the contraction of the vas deferens produced by electrical transmural stimulation. On the other hand, Mitragynine failed to affect the responses to norepinephrine and ATP. Mitragynine did not reduce KCl-induced contraction in the presence of tetrodotoxin, prazosin and α,β-methylene ATP. Mitragynine inhibited nicotine- or tyramine-induced contraction. By using the patch-clamp technique, Mitragynine was found to block T- and L-type Ca 2+ channel currents in N1E-115 neuroblastoma cells. In the Ca 2+ measurement by a fluorescent dye method, Mitragynine reduced KCl-induced Ca 2+ influx in neuroblastoma cells. The present results suggest that Mitragynine inhibits the vas deferens contraction elicited by nerve stimulation, probably through its blockade of neuronal Ca 2+ channels.
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indole alkaloids of a thai medicinal herb mitragyna speciosa that has opioid agonistic effect in guinea pig ileum
Planta Medica, 2005Co-Authors: Syunji Horie, Hiromitsu Takayama, Norio Aimi, Dhavadee Ponglux, Hayato Ishikawa, Kenjiro Matsumoto, Fumi Koyama, Toshihiko MurayamaAbstract:Recently, we found that Mitragynine, a major constituent of Mitragyna speciosa, has an opioid agonistic activity, but its weak potency could not explain the opium-like effect of this plant. In the present study, bioassay-guided fractionation of the crude extract of the leaves of M. speciosa was carried out to search for potent opioid agonists other than Mitragynine. Opioid agonistic activities were evaluated using twitch contraction induced by electrical stimulation in guinea-pig ileum. The crude extract of M. speciosa inhibited the twitch contraction in a concentration-dependent manner. The inhibition was reversed by naloxone. The opioid effect was detected only in the crude base fraction, which was followed by the isolation of five indole alkaloids. Among these alkaloids, 7-hydroxyMitragynine showed the most potent opioid effect on the electrically-stimulated contraction (pD (2) = 8.38 +/- 0.12). The potency, calculated using pD (2) values, was 30- and 17-fold higher than that of Mitragynine and morphine, respectively. Antagonism of naloxone on concentration-response curves for 7-hydroxyMitragynine confirmed its opioid effect. These results suggest that the opioid effect of M. speciosa is mostly based on the activity of 7-hydroxyMitragynine.
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opioid receptor agonistic characteristics of Mitragynine pseudoindoxyl in comparison with Mitragynine derived from thai medicinal plant mitragyna speciosa
General Pharmacology-the Vascular System, 1999Co-Authors: Leonardo T Yamamoto, Shinichiro Sakai, Hiromitsu Takayama, Norio Aimi, Shingo Yano, Syunji Horie, Dhavadee Ponglux, Jie Shan, Peter K T Pang, Kazuo WatanabeAbstract:Abstract We have previously elucidated the opiate-like action of Mitragynine, an active principle isolated from the Thai medicinal plant Mitragyna speciosa. In the present study, effects of the related compound, Mitragynine pseudoindoxyl on electrically stimulated contraction in guinea pig ileum and mouse vas deferens, and on its binding affinity in the guinea pig brain membranes were studied. Mitragynine pseudoindoxyl inhibited the electrically stimulated ileum and mouse vas deferens contractions in a concentration-dependent manner. In the ileum, the effective concentration is in an nM order, being nearly equivalent to reported concentrations of the μ-opioid receptor agonist [D-Ala2, Met-Phe4, Gly-ol5] enkephalin (DAMGO), and is 100- and 20-fold smaller than those of Mitragynine and morphine, respectively. In the vas deferens, it is 35-fold smaller than that of morphine. The inhibitory action of Mitragynine pseudoindoxyl in the ileum was antagonized by the non-selective opioid receptor antagonist naloxone and the μ-receptor antagonist naloxonazine. It was also antagonized by the δ-receptor antagonist naltrindole in the vas deferens. Mitragynine pseudoindoxyl showed a similar binding affinity to DAMGO and naltrindole at μ- and δ-receptors, respectively. However, the affinity at κ-receptors was negligible. The present study demonstrates that Mitragynine pseudoindoxyl, a novel alkaloid structurally different from other opioid agonists, acts on opioid receptors, leading to a potent inhibition of electrically stimulated contraction in the ileum through the μ-receptors and in mouse vas deferens through δ-receptors.
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inhibitory effect of Mitragynine an alkaloid with analgesic effect from thai medicinal plant mitragyna speciosa on electrically stimulated contraction of isolated guinea pig ileum through the opioid receptor
Life Sciences, 1997Co-Authors: Kazuo Watanabe, Shingo Yano, Syunji Horie, Leonardo T YamamotoAbstract:Abstract Effect of Mitragynine, an indole alkaloid isolated from Thai medicinal plant kratom ( Mitragyna speciosa ), on electrically stimulated contraction was studied in the guinea-pig ileum. Mitragynine (1 nM - 3 μM) inhibited the ileum contraction elicited by electrical stimulation, and its pD 2 value was 6.91 ± 0.04 (n = 5). Morphine (1 nM − 1 μM) also inhibited the electrically stimulated contraction in a concentration-dependent manner (pD 2 7.68 ± 0.11; n = 5). Mitragynine was 10 fold less potent than morphine. Mitragynine (3–10 μM) did not show any effect on the smooth muscle contraction induced by acetylcholine or histamine. Naloxone (10–300 nM) reversed the inhibitory effect of Mitragynine on electrically stimulated contraction. Furthermore, naloxone showed a shift of concentration-response curve of Mitragynine to the right. There was no significant difference in the affinity of naloxone (i.e. pA 2 ) in the presence of Mitragynine or morphine. Mitragynine (3–10 μM) inhibited the naloxone-precipitated withdrawal contraction following a brief (5 min) exposure of the ileum to morphine. Tetrodotoxin (1 μM) and atropine (1 μM) inhibited the withdrawal contraction. The present results suggest that Mitragynine inhibits the electrically stimulated contraction of guinea-pig ileum through the opioid receptor.
Surash Ramanathan - One of the best experts on this subject based on the ideXlab platform.
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combinations of indole based alkaloids from mitragyna speciosa kratom and cisplatin inhibit cell proliferation and migration of nasopharyngeal carcinoma cell lines
Journal of Ethnopharmacology, 2021Co-Authors: Gregory Domnic, Surash Ramanathan, Nelson Jeng Yeou Chear, Siti Fairus Abdul Rahman, Darshan Singh, Nethia MohanakumaranAbstract:Abstract Ethnopharmacological relevance Mitragyna speciosa (Korth.) or kratom is a medicinal plant indigenous to Southeast Asia. The leaf of M. speciosa is used as a remedy in pain management including cancer related pain, in a similar way as opioids and cannabis. Despite its well-known analgesic effect, there is a scarce of information on the cancer-suppressing potential of M. speciosa and its active constituents. Aim of the study To assess the potential applicability of M. speciosa alkaloids (Mitragynine, speciociliatine or paynantheine) as chemosensitizers for cisplatin in Nasopharyngeal carcinoma (NPC) cell lines. Materials and methods The cytotoxic effects of the extracts, fractions and compounds were determined by conducting in vitro cytotoxicity assays. Based on the cytotoxic screening, the alkaloid extract of M. speciosa exhibited potent inhibitory effect on the NPC cell line NPC/HK1, and therefore, was chosen for further fractionation and purification. NPC cell lines NPC/HK1 and C666-1 were treated with combinations of cisplatin and M. speciosa alkaloids combinations in 2D monolayer culture. The effect of cisplatin and Mitragynine as a combination on cell migration was tested using in vitro wound healing and spheroid invasion assays. Results In our bioassay guided isolation, both methanolic and alkaloid extracts showed mild to moderate cytotoxic effect against the NPC/HK1 cell line. Both NPC cell lines (NPC/HK1 and C666-1) were insensitive to single agent and combination treatments of the M. speciosa alkaloids. However, Mitragynine and speciociliatine sensitized the NPC/HK1 and C666-1 cells to cisplatin at ~4- and >5-fold, respectively in 2D monolayer culture. The combination of Mitragynine and cisplatin also significantly inhibited cell migration of the NPC cell lines. Similarly, the combination also of Mitragynine and cisplatin inhibited growth and invasion of NPC/HK1 spheroids in a dose-dependent manner. In addition, the spheroids did not rapidly develop resistance to the drug combinations at higher concentrations over 10 days. Conclusion Our data indicate that both Mitragynine and speciociliatine could be potential chemosensitizers for cisplatin. Further elucidation focusing on the drug mechanistic studies and in vivo studies are necessary to support delineate the therapeutic applicability of M. speciosa alkaloids for NPC treatment.
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Accelerated Solvent Extractions (ASE) of Mitragyna speciosa Korth. (Kratom) Leaves: Evaluation of Its Cytotoxicity and Antinociceptive Activity
'MDPI AG', 2021Co-Authors: Yong Sean Goh, Thiruventhan Karunakaran, Vikneswaran Murugaiyah, Rameshkumar Santhanam, Mohamad Hafizi Abu Bakar, Surash RamanathanAbstract:Mitragyna speciosa Korth (kratom) is known for its psychoactive and analgesic properties. Mitragynine is the primary constituent present in kratom leaves. This study highlights the utilisation of the green accelerated solvent extraction technique to produce a better, non-toxic and antinociceptive active botanical extract of kratom. ASE M. speciosa extract had a dry yield (0.53–2.91 g) and showed a constant Mitragynine content (6.53–7.19%) when extracted with organic solvents of different polarities. It only requires a shorter extraction time (5 min) and a reduced amount of solvents (less than 100 mL). A substantial amount of total phenolic (407.83 ± 2.50 GAE mg/g and flavonoids (194.00 ± 5.00 QE mg/g) were found in ASE kratom ethanol extract. The MTT test indicated that the ASE kratom ethanolic leaf extract is non-cytotoxic towards HEK-293 and HeLa Chang liver cells. In mice, ASE kratom ethanolic extract (200 mg/kg) demonstrated a better antinociceptive effect compared to methanol and ethyl acetate leaf extracts. The presence of bioactive indole alkaloids and flavonols such as Mitragynine, paynantheine, quercetin, and rutin in ASE kratom ethanolic leaf extract was detected using UHPLC-ESI-QTOF-MS/MS analysis supports its antinociceptive properties. ASE ethanolic leaf extract offers a better, safe, and cost-effective choice of test botanical extract for further preclinical studies
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DataSheet1_Comparative Toxicity Assessment of Kratom Decoction, Mitragynine and Speciociliatine Versus Morphine on Zebrafish (Danio rerio) Embryos.docx
'Frontiers Media SA', 2021Co-Authors: Thenmoly Damodaran, Nelson Jeng Yeou Chear, Vikneswaran Murugaiyah, Mohd Nizam Mordi, Surash RamanathanAbstract:Background: Kratom (Mitragyna speciosa Korth), a popular opioid-like plant holds its therapeutic potential in pain management and opioid dependence. However, there are growing concerns about the safety or potential toxicity risk of kratom after prolonged use.Aim of the study: The study aimed to assess the possible toxic effects of kratom decoction and its major alkaloids, Mitragynine, and speciociliatine in comparison to morphine in an embryonic zebrafish model.Methods: The zebrafish embryos were exposed to kratom decoction (1,000–62.5 μg/ml), Mitragynine, speciociliatine, and morphine (100–3.125 μg/ml) for 96 h post-fertilization (hpf). The toxicity parameters, namely mortality, hatching rate, heart rate, and morphological malformations were examined at 24, 48, 72, and 96 hpf, respectively.Results: Kratom decoction at a concentration range of ≥500 μg/ml caused 100% mortality of zebrafish embryos and decreased the hatching rate in a concentration-dependent manner. Meanwhile, Mitragynine and speciociliatine exposure resulted in 100% mortality of zebrafish embryos at 100 μg/ml. Both alkaloids caused significant alterations in the morphological development of zebrafish embryos including hatching inhibition and spinal curvature (scoliosis) at the highest concentration. While exposure to morphine induced significant morphological malformations such as pericardial oedema, spinal curvature (lordosis), and yolk edema in zebrafish embryos.Conclusion: Our findings provide evidence for embryonic developmental toxicity of kratom decoction and its alkaloids both Mitragynine and speciociliatine at the highest concentration, hence suggesting that kratom consumption may have potential teratogenicity risk during pregnancy and thereby warrants further investigations.
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Comparative Toxicity Assessment of Kratom Decoction, Mitragynine and Speciociliatine Versus Morphine on Zebrafish (Danio rerio) Embryos
'Frontiers Media SA', 2021Co-Authors: Thenmoly Damodaran, Nelson Jeng Yeou Chear, Vikneswaran Murugaiyah, Mohd Nizam Mordi, Surash RamanathanAbstract:Background: Kratom (Mitragyna speciosa Korth), a popular opioid-like plant holds its therapeutic potential in pain management and opioid dependence. However, there are growing concerns about the safety or potential toxicity risk of kratom after prolonged use.Aim of the study: The study aimed to assess the possible toxic effects of kratom decoction and its major alkaloids, Mitragynine, and speciociliatine in comparison to morphine in an embryonic zebrafish model.Methods: The zebrafish embryos were exposed to kratom decoction (1,000–62.5 μg/ml), Mitragynine, speciociliatine, and morphine (100–3.125 μg/ml) for 96 h post-fertilization (hpf). The toxicity parameters, namely mortality, hatching rate, heart rate, and morphological malformations were examined at 24, 48, 72, and 96 hpf, respectively.Results: Kratom decoction at a concentration range of ≥500 μg/ml caused 100% mortality of zebrafish embryos and decreased the hatching rate in a concentration-dependent manner. Meanwhile, Mitragynine and speciociliatine exposure resulted in 100% mortality of zebrafish embryos at 100 μg/ml. Both alkaloids caused significant alterations in the morphological development of zebrafish embryos including hatching inhibition and spinal curvature (scoliosis) at the highest concentration. While exposure to morphine induced significant morphological malformations such as pericardial oedema, spinal curvature (lordosis), and yolk edema in zebrafish embryos.Conclusion: Our findings provide evidence for embryonic developmental toxicity of kratom decoction and its alkaloids both Mitragynine and speciociliatine at the highest concentration, hence suggesting that kratom consumption may have potential teratogenicity risk during pregnancy and thereby warrants further investigations
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understanding the physicochemical properties of Mitragynine a principal alkaloid of mitragyna speciosa for preclinical evaluation
Molecules, 2015Co-Authors: Surash Ramanathan, Suhanya Parthasarathy, Vikneswaran Murugaiyah, Enrico Magosso, Soo Choon Tan, Sharif Mahsufi MansorAbstract:Varied pharmacological responses have been reported for Mitragynine in the literature, but no supportive scientific explanations have been given for this. These studies have been undertaken without a sufficient understanding of the physicochemical properties of Mitragynine. In this work a UV spectrophotometer approach and HPLC-UV method were employed to ascertain the physicochemical properties of Mitragynine. The pKa of Mitragynine measured by conventional UV (8.11 ± 0.11) was in agreement with the microplate reader determination (8.08 ± 0.04). Mitragynine is a lipophilic alkaloid, as indicated by a logP value of 1.73. Mitragynine had poor solubility in water and basic media, and conversely in acidic environments, but it is acid labile. In an in vitro dissolution the total drug release was higher for the simulated gastric fluid but was prolonged and incomplete for the simulated intestinal fluid. The hydrophobicity, poor water solubility, high variability of drug release in simulated biological fluids and acid degradable characteristics of Mitragynine probably explain the large variability of its pharmacological responses reported in the literature. The determined physicochemical properties of Mitragynine will provide a basis for developing a suitable formulation to further improve its solubility, stability and oral absorption for better assessment of this compound in preclinical studies.
Hiromitsu Takayama - One of the best experts on this subject based on the ideXlab platform.
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Simultaneous analysis of Mitragynine, 7-hydroxyMitragynine, and other alkaloids in the psychotropic plant “kratom” (Mitragyna speciosa) by LC-ESI-MS
Forensic Toxicology, 2009Co-Authors: Ruri Kikura-hanajiri, Hiromitsu Takayama, Mariko Kitajima, Maiko Kawamura, Takuro Maruyama, Yukihiro GodaAbstract:The leaves of Mitragyna speciosa , a tropical plant known as “kratom,” have been traditionally used as a substitute for opium in Thailand and Malaysia. Mitragynine, a major constituent of M. speciosa , has an opioid agonistic activity, and its derivative 7-hydroxyMitragynine (7-OH-Mitragynine) (a minor constituent) is much more potent than Mitragynine or morphine. Recently, many products containing this plant have been distributed as “incense” on the drug market in Japan for their expected narcotic effects. Despite their potency and their wide distribution for abuse, there are no reports on the quantitative analysis of Mitragynine and 7-OH-Mitragynine in the raw materials or in the commercial products of kratom. In this study, a method for simultaneous analysis of Mitragynine, 7-OH-Mitragynine, and other indole alkaloids (speciogynine, speciociliatine, and paynantheine), present in the raw materials and commercial products of kratom, was developed using liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS). By this method, Mitragynine, 7-OH-Mitragynine, and the other alkaloids were detected in 11 of the 13 products. The content of Mitragynine in the products ranged from 1% to 6%, and that of 7-OH-Mitragynine from 0.01% to 0.04%. Because 7-OH-Mitragynine is much more potent than morphine, M. speciosa abuse is a matter of major concern. The present analytical method is considered useful for the screening of M. speciosa products in the drug market.
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inhibitory effect of Mitragynine an analgesic alkaloid from thai herbal medicine on neurogenic contraction of the vas deferens
Life Sciences, 2005Co-Authors: Kenjiro Matsumoto, Hiromitsu Takayama, Kazuo Watanabe, Shingo Yano, Syunji Horie, Leonardo T Yamamoto, Dhavadee Ponglux, Jie Shan, Peter K T PangAbstract:Abstract The effect of an indole-alkaloid Mitragynine isolated from the Thai medicinal herb kratom ( Mitragyna speciosa ) on neurogenic contraction of smooth muscle was studied in guinea-pig vas deferens. Mitragynine inhibited the contraction of the vas deferens produced by electrical transmural stimulation. On the other hand, Mitragynine failed to affect the responses to norepinephrine and ATP. Mitragynine did not reduce KCl-induced contraction in the presence of tetrodotoxin, prazosin and α,β-methylene ATP. Mitragynine inhibited nicotine- or tyramine-induced contraction. By using the patch-clamp technique, Mitragynine was found to block T- and L-type Ca 2+ channel currents in N1E-115 neuroblastoma cells. In the Ca 2+ measurement by a fluorescent dye method, Mitragynine reduced KCl-induced Ca 2+ influx in neuroblastoma cells. The present results suggest that Mitragynine inhibits the vas deferens contraction elicited by nerve stimulation, probably through its blockade of neuronal Ca 2+ channels.
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indole alkaloids of a thai medicinal herb mitragyna speciosa that has opioid agonistic effect in guinea pig ileum
Planta Medica, 2005Co-Authors: Syunji Horie, Hiromitsu Takayama, Norio Aimi, Dhavadee Ponglux, Hayato Ishikawa, Kenjiro Matsumoto, Fumi Koyama, Toshihiko MurayamaAbstract:Recently, we found that Mitragynine, a major constituent of Mitragyna speciosa, has an opioid agonistic activity, but its weak potency could not explain the opium-like effect of this plant. In the present study, bioassay-guided fractionation of the crude extract of the leaves of M. speciosa was carried out to search for potent opioid agonists other than Mitragynine. Opioid agonistic activities were evaluated using twitch contraction induced by electrical stimulation in guinea-pig ileum. The crude extract of M. speciosa inhibited the twitch contraction in a concentration-dependent manner. The inhibition was reversed by naloxone. The opioid effect was detected only in the crude base fraction, which was followed by the isolation of five indole alkaloids. Among these alkaloids, 7-hydroxyMitragynine showed the most potent opioid effect on the electrically-stimulated contraction (pD (2) = 8.38 +/- 0.12). The potency, calculated using pD (2) values, was 30- and 17-fold higher than that of Mitragynine and morphine, respectively. Antagonism of naloxone on concentration-response curves for 7-hydroxyMitragynine confirmed its opioid effect. These results suggest that the opioid effect of M. speciosa is mostly based on the activity of 7-hydroxyMitragynine.
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chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant mitragyna speciosa
Chemical & Pharmaceutical Bulletin, 2004Co-Authors: Hiromitsu TakayamaAbstract:The leaves of a tropical plant, Mitragyna speciosa KORTH (Rubiaceae), have been traditionally used as a substitute for opium. Phytochemical studies of the constituents of the plant growing in Thailand and Malaysia have led to the isolation of several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids, including new natural products. The structures of the new compounds were elucidated by spectroscopic and/or synthetic methods. The potent opioid agonistic activities of Mitragynine, the major constituent of this plant, and its analogues were found in in vitro and in vivo experiments and the mechanisms underlying the analgesic activity were clarified. The essential structural features of Mitragynines, which differ from those of morphine and are responsible for the analgesic activity, were elucidated by pharmacological evaluation of the natural and synthetic derivatives. Among the Mitragynine derivatives, 7-hydroxyMitragynine, a minor constituent of M. speciosa, was found to exhibit potent antinociceptive activity in mice.
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Chem. Pharm. Bull. 52(8) 916-928 (2004)
2004Co-Authors: Hiromitsu Takayama, International AcademicAbstract:The leaves of a tropical plant, Mitragyna speciosa KORTH (Rubiaceae), have been traditionally used as a substitute for opium. Phytochemical studies of the constituents of the plant growing in Thailand and Malaysia have led to the isolation of several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids, including new natural products. The structures of the new compounds were elucidated by spectroscopic and/or synthetic methods. The potent opioid agonistic activities of Mitragynine, the major constituent of this plant, and its analogues were found in in vitro and in vivo experiments and the mechanisms underlying the analgesic activity were clarified. The essential structural features of Mitragynines, which differ from those of morphine and are responsible for the analgesic activity, were elucidated by pharmacological evaluation of the natural and synthetic derivatives. Among the Mitragynine derivatives, 7-hydroxyMitragynine, a minor constituent of M. speciosa, was found to exhibit potent antinociceptive activity in mice
Leonardo T Yamamoto - One of the best experts on this subject based on the ideXlab platform.
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inhibitory effect of Mitragynine an analgesic alkaloid from thai herbal medicine on neurogenic contraction of the vas deferens
Life Sciences, 2005Co-Authors: Kenjiro Matsumoto, Hiromitsu Takayama, Kazuo Watanabe, Shingo Yano, Syunji Horie, Leonardo T Yamamoto, Dhavadee Ponglux, Jie Shan, Peter K T PangAbstract:Abstract The effect of an indole-alkaloid Mitragynine isolated from the Thai medicinal herb kratom ( Mitragyna speciosa ) on neurogenic contraction of smooth muscle was studied in guinea-pig vas deferens. Mitragynine inhibited the contraction of the vas deferens produced by electrical transmural stimulation. On the other hand, Mitragynine failed to affect the responses to norepinephrine and ATP. Mitragynine did not reduce KCl-induced contraction in the presence of tetrodotoxin, prazosin and α,β-methylene ATP. Mitragynine inhibited nicotine- or tyramine-induced contraction. By using the patch-clamp technique, Mitragynine was found to block T- and L-type Ca 2+ channel currents in N1E-115 neuroblastoma cells. In the Ca 2+ measurement by a fluorescent dye method, Mitragynine reduced KCl-induced Ca 2+ influx in neuroblastoma cells. The present results suggest that Mitragynine inhibits the vas deferens contraction elicited by nerve stimulation, probably through its blockade of neuronal Ca 2+ channels.
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opioid receptor agonistic characteristics of Mitragynine pseudoindoxyl in comparison with Mitragynine derived from thai medicinal plant mitragyna speciosa
General Pharmacology-the Vascular System, 1999Co-Authors: Leonardo T Yamamoto, Shinichiro Sakai, Hiromitsu Takayama, Norio Aimi, Shingo Yano, Syunji Horie, Dhavadee Ponglux, Jie Shan, Peter K T Pang, Kazuo WatanabeAbstract:Abstract We have previously elucidated the opiate-like action of Mitragynine, an active principle isolated from the Thai medicinal plant Mitragyna speciosa. In the present study, effects of the related compound, Mitragynine pseudoindoxyl on electrically stimulated contraction in guinea pig ileum and mouse vas deferens, and on its binding affinity in the guinea pig brain membranes were studied. Mitragynine pseudoindoxyl inhibited the electrically stimulated ileum and mouse vas deferens contractions in a concentration-dependent manner. In the ileum, the effective concentration is in an nM order, being nearly equivalent to reported concentrations of the μ-opioid receptor agonist [D-Ala2, Met-Phe4, Gly-ol5] enkephalin (DAMGO), and is 100- and 20-fold smaller than those of Mitragynine and morphine, respectively. In the vas deferens, it is 35-fold smaller than that of morphine. The inhibitory action of Mitragynine pseudoindoxyl in the ileum was antagonized by the non-selective opioid receptor antagonist naloxone and the μ-receptor antagonist naloxonazine. It was also antagonized by the δ-receptor antagonist naltrindole in the vas deferens. Mitragynine pseudoindoxyl showed a similar binding affinity to DAMGO and naltrindole at μ- and δ-receptors, respectively. However, the affinity at κ-receptors was negligible. The present study demonstrates that Mitragynine pseudoindoxyl, a novel alkaloid structurally different from other opioid agonists, acts on opioid receptors, leading to a potent inhibition of electrically stimulated contraction in the ileum through the μ-receptors and in mouse vas deferens through δ-receptors.
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inhibitory effect of Mitragynine an alkaloid with analgesic effect from thai medicinal plant mitragyna speciosa on electrically stimulated contraction of isolated guinea pig ileum through the opioid receptor
Life Sciences, 1997Co-Authors: Kazuo Watanabe, Shingo Yano, Syunji Horie, Leonardo T YamamotoAbstract:Abstract Effect of Mitragynine, an indole alkaloid isolated from Thai medicinal plant kratom ( Mitragyna speciosa ), on electrically stimulated contraction was studied in the guinea-pig ileum. Mitragynine (1 nM - 3 μM) inhibited the ileum contraction elicited by electrical stimulation, and its pD 2 value was 6.91 ± 0.04 (n = 5). Morphine (1 nM − 1 μM) also inhibited the electrically stimulated contraction in a concentration-dependent manner (pD 2 7.68 ± 0.11; n = 5). Mitragynine was 10 fold less potent than morphine. Mitragynine (3–10 μM) did not show any effect on the smooth muscle contraction induced by acetylcholine or histamine. Naloxone (10–300 nM) reversed the inhibitory effect of Mitragynine on electrically stimulated contraction. Furthermore, naloxone showed a shift of concentration-response curve of Mitragynine to the right. There was no significant difference in the affinity of naloxone (i.e. pA 2 ) in the presence of Mitragynine or morphine. Mitragynine (3–10 μM) inhibited the naloxone-precipitated withdrawal contraction following a brief (5 min) exposure of the ileum to morphine. Tetrodotoxin (1 μM) and atropine (1 μM) inhibited the withdrawal contraction. The present results suggest that Mitragynine inhibits the electrically stimulated contraction of guinea-pig ileum through the opioid receptor.
Norio Aimi - One of the best experts on this subject based on the ideXlab platform.
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indole alkaloids of a thai medicinal herb mitragyna speciosa that has opioid agonistic effect in guinea pig ileum
Planta Medica, 2005Co-Authors: Syunji Horie, Hiromitsu Takayama, Norio Aimi, Dhavadee Ponglux, Hayato Ishikawa, Kenjiro Matsumoto, Fumi Koyama, Toshihiko MurayamaAbstract:Recently, we found that Mitragynine, a major constituent of Mitragyna speciosa, has an opioid agonistic activity, but its weak potency could not explain the opium-like effect of this plant. In the present study, bioassay-guided fractionation of the crude extract of the leaves of M. speciosa was carried out to search for potent opioid agonists other than Mitragynine. Opioid agonistic activities were evaluated using twitch contraction induced by electrical stimulation in guinea-pig ileum. The crude extract of M. speciosa inhibited the twitch contraction in a concentration-dependent manner. The inhibition was reversed by naloxone. The opioid effect was detected only in the crude base fraction, which was followed by the isolation of five indole alkaloids. Among these alkaloids, 7-hydroxyMitragynine showed the most potent opioid effect on the electrically-stimulated contraction (pD (2) = 8.38 +/- 0.12). The potency, calculated using pD (2) values, was 30- and 17-fold higher than that of Mitragynine and morphine, respectively. Antagonism of naloxone on concentration-response curves for 7-hydroxyMitragynine confirmed its opioid effect. These results suggest that the opioid effect of M. speciosa is mostly based on the activity of 7-hydroxyMitragynine.
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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, 2002Co-Authors: Hayato Ishikawa, Norio Aimi, Mariko Kitajima, Dhavadee Ponglux, Kenjiro Matsumoto, Mika Kurihara, Fumi Koyama, Tomoyuki Moriyama, Leonard T YamamotoAbstract:Mitragynine (1) is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa, and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compound, synthesis of some derivatives, evaluations of the structure−activity relationship, and surveys of the intrinsic activities and potencies on opioid receptors were performed with guinea pig ileum. The affinities of some compounds for μ-, δ-, and κ-receptors were determined in a receptor binding assay. The essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were also clarified. The oxidative derivatives of Mitragynine, i.e., Mitragynine pseudoindoxyl (2) and 7-hydroxyMitragynine (12), were found as opioid agonists with higher potency than morphine in the experiment with guinea pig ileum. In addition, 2 induced an analgesic activity in the tail flick test in mice.
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Structure revision of mitragynaline, an indole alkaloid in Mitragyna speciosa
Tetrahedron Letters, 2001Co-Authors: Hayato Ishikawa, Norio Aimi, Mariko Kitajima, Mika Kurihara, Ikram M. Said, Hiroko Seki, Kentaro Yamaguchi, Peter J. HoughtonAbstract:Abstract The structure of mitragynaline, an indole alkaloid isolated from Malaysian Mitragyna speciosa , was revised as formula 3 by analysis of the NMR spectra measured at low temperature and by chemical transformation with DDQ oxidation from the known alkaloid Mitragynine ( 5 ).
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Chemical studies on the analgesic indole alkaloids from the traditional medicine (Mitragyna speciosa) used for opium substitute
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 2000Co-Authors: Norio AimiAbstract:The leaves of a tropical plant, Mitragyna speciosa Korth. (Rubiaceae), have been traditionally used as a substitute for opium. By phytochemical studies on the constituents of the plant growing in Thailand as well as in Malaysia, several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids including new natural products were isolated. The structures of these new compounds were elucidated by the modern spectroscopic methods and/or chiral-total syntheses. The chiral total synthesis of (-)-Mitragynine, a major component of this plant, was achieved. Potent opioid agonistic properties of Mitragynine, which acts on mu- and delta-opioid subtype receptors, and of Mitragynine pseudoindoxyl, whose analgesic activity is more potent than that of morphine, were clarified in in vitro experiments. The essential structural features in Mitragynine for revealing the analgesic activity were elucidated by pharmacological evaluation of the natural and synthetic Mitragynine derivatives.
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opioid receptor agonistic characteristics of Mitragynine pseudoindoxyl in comparison with Mitragynine derived from thai medicinal plant mitragyna speciosa
General Pharmacology-the Vascular System, 1999Co-Authors: Leonardo T Yamamoto, Shinichiro Sakai, Hiromitsu Takayama, Norio Aimi, Shingo Yano, Syunji Horie, Dhavadee Ponglux, Jie Shan, Peter K T Pang, Kazuo WatanabeAbstract:Abstract We have previously elucidated the opiate-like action of Mitragynine, an active principle isolated from the Thai medicinal plant Mitragyna speciosa. In the present study, effects of the related compound, Mitragynine pseudoindoxyl on electrically stimulated contraction in guinea pig ileum and mouse vas deferens, and on its binding affinity in the guinea pig brain membranes were studied. Mitragynine pseudoindoxyl inhibited the electrically stimulated ileum and mouse vas deferens contractions in a concentration-dependent manner. In the ileum, the effective concentration is in an nM order, being nearly equivalent to reported concentrations of the μ-opioid receptor agonist [D-Ala2, Met-Phe4, Gly-ol5] enkephalin (DAMGO), and is 100- and 20-fold smaller than those of Mitragynine and morphine, respectively. In the vas deferens, it is 35-fold smaller than that of morphine. The inhibitory action of Mitragynine pseudoindoxyl in the ileum was antagonized by the non-selective opioid receptor antagonist naloxone and the μ-receptor antagonist naloxonazine. It was also antagonized by the δ-receptor antagonist naltrindole in the vas deferens. Mitragynine pseudoindoxyl showed a similar binding affinity to DAMGO and naltrindole at μ- and δ-receptors, respectively. However, the affinity at κ-receptors was negligible. The present study demonstrates that Mitragynine pseudoindoxyl, a novel alkaloid structurally different from other opioid agonists, acts on opioid receptors, leading to a potent inhibition of electrically stimulated contraction in the ileum through the μ-receptors and in mouse vas deferens through δ-receptors.
