Displaying publications 1 - 20 of 31 in total

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  1. Baclofen blocks the acquisition and expression of mitragynine-induced conditioned place preference in rats
    Yusoff NHM, Mansor SM, Müller CP, Hassan Z
    Behav Brain Res, 2018 06 01;345:65-71.
    PMID: 29499286 DOI: 10.1016/j.bbr.2018.02.039
    Mitragynine is the major alkaloid found in the leaves of M. speciosa Korth (Rubiaceae), a plant that is native to Southeast Asia. This compound has been used, either traditionally or recreationally, due to its psychostimulant and opioid-like effects. Recently, mitragynine has been shown to exert conditioned place preference (CPP), indicating the rewarding and motivational properties of M. speciosa. Here, the involvement of GABAB receptors in mediating mitragynine reward is studied using a CPP paradigm in rats. First, we examined the effects of GABAB receptor agonist baclofen (1.25, 2.5 and 5 mg/kg) on the acquisition of mitragynine (10 mg/kg)-induced CPP. Second, the involvement of GABAB receptors in the expression of mitragynine-induced CPP was tested. We found that the acquisition of mitragynine-induced CPP could be blocked by higher doses (2.5 and 5 mg/kg) of baclofen. Baclofen at a high dose inhibited locomotor activity and caused a CPP. Furthermore, we found that baclofen (2.5 and 5 mg/kg) also blocked the expression of mitragynine-induced CPP. These findings suggest that both, the acquisition and expression of mitragynine's reinforcing properties is controlled by the GABAB receptor.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  2. Opioid receptors mediate the acquisition, but not the expression of mitragynine-induced conditioned place preference in rats
    Yusoff NHM, Mansor SM, Müller CP, Hassan Z
    Behav Brain Res, 2017 08 14;332:1-6.
    PMID: 28559179 DOI: 10.1016/j.bbr.2017.05.059
    Mitragynine is the main psychoactive ingredient of the herbal drug preparation Kratom (Ketum), derived from the plant Mitragyna speciosa. Kratom is a widely abused drug in Southeast Asian and has a psychostimulant profile at low-medium doses, while high doses have opioidergic effects. Mitragynine was shown to possess opiate receptor affinity. However, its role in the behavioural effects of mitragynine is unclear. Here we asked whether the reinforcing effects of mitragynine are mediated by opiate receptors using a conditioned place preference (CPP) paradigm in rats. In the first experiment we tested the effects of the opiate receptor antagonist naloxone (0.1, 0.3 and 1.0mg/kg) on the acquisition of mitragynine (10mg/kg)-induced CPP. In the second experiment, we tested the involvement of opiate receptors in the expression of mitragynine-induced CPP in rats. We found that naloxone suppresses the acquisition of mitragynine-induced CPP. This effect was already evident at a dose of naloxone (0.1mg/kg) which, by itself, had no conditioned place aversion (CPA) effect. Higher doses of naloxone induced a CPA and blocked mitragynine-induced CPP. In contrast, naloxone had no effect on the expression of mitragynine-induced CPP. These findings suggest that the acquisition, but not the expression of the reinforcing effects of mitragynine is mediated by opiate receptors.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  3. Abuse potential and adverse cognitive effects of mitragynine (kratom)
    Yusoff NH, Suhaimi FW, Vadivelu RK, Hassan Z, Rümler A, Rotter A, et al.
    Addict Biol, 2016 Jan;21(1):98-110.
    PMID: 25262913 DOI: 10.1111/adb.12185
    Mitragynine is the major psychoactive alkaloid of the plant kratom/ketum. Kratom is widely used in Southeast Asia as a recreational drug, and increasingly appears as a pure compound or a component of 'herbal high' preparations in the Western world. While mitragynine/kratom may have analgesic, muscle relaxant and anti-inflammatory effects, its addictive properties and effects on cognitive performance are unknown. We isolated mitragynine from the plant and performed a thorough investigation of its behavioural effects in rats and mice. Here we describe an addictive profile and cognitive impairments of acute and chronic mitragynine administration, which closely resembles that of morphine. Acute mitragynine has complex effects on locomotor activity. Repeated administration induces locomotor sensitization, anxiolysis and conditioned place preference, enhances expression of dopamine transporter- and dopamine receptor-regulating factor mRNA in the mesencephalon. While there was no increase in spontaneous locomotor activity during withdrawal, animals showed hypersensitivity towards small challenging doses for up to 14 days. Severe somatic withdrawal signs developed after 12 hours, and increased level of anxiety became evident after 24 hours of withdrawal. Acute mitragynine independently impaired passive avoidance learning, memory consolidation and retrieval, possibly mediated by a disruption of cortical oscillatory activity, including the suppression of low-frequency rhythms (delta and theta) in the electrocorticogram. Chronic mitragynine administration led to impaired passive avoidance and object recognition learning. Altogether, these findings provide evidence for an addiction potential with cognitive impairments for mitragynine, which suggest its classification as a harmful drug.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  4. Mitragynine inhibits the COX-2 mRNA expression and prostaglandin E₂ production induced by lipopolysaccharide in RAW264.7 macrophage cells
    Utar Z, Majid MI, Adenan MI, Jamil MF, Lan TM
    J Ethnopharmacol, 2011 Jun 14;136(1):75-82.
    PMID: 21513785 DOI: 10.1016/j.jep.2011.04.011
    ETHNOPHARMACOLOGICAL RELEVANCE: [corrected] Mitragyna speciosa Korth (Rubiaceae) is one of the medicinal plants used traditionally to treat various types of diseases especially in Thailand and Malaysia. Its anti-inflammatory and analgesic properties in its crude form are well documented. In this study, the cellular mechanism involved in the anti-inflammatory effects of mitragynine, the major bioactive constituent, was investigated.

    MATERIALS AND METHODS: The effects of mitragynine on the mRNA and protein expression of COX-1 and COX-2 and the production of prostaglandin E(2) (PGE(2)) were investigated in LPS-treated RAW264.7 macrophage cells. Quantitative RT-PCR was used to assess the mRNA expression of COX-1 and COX-2. Protein expression of COX-1 and COX-2 were assessed using Western blot analysis and the level of PGE(2) production was quantified using Parameter™ PGE(2) Assay (R&D Systems).

    RESULTS: Mitragynine produced a significant inhibition on the mRNA expression of COX-2 induced by LPS, in a dose dependent manner and this was followed by the reduction of PGE(2) production. On the other hand, the effects of mitragynine on COX-1 mRNA expression were found to be insignificant as compared to the control cells. However, the effect of mitragynine on COX-1 protein expression is dependent on concentration, with higher concentration of mitragynine producing a further reduction of COX-1 expression in LPS-treated cells.

    CONCLUSIONS: These findings suggest that mitragynine suppressed PGE(2) production by inhibiting COX-2 expression in LPS-stimulated RAW264.7 macrophage cells. Mitragynine may be useful for the treatment of inflammatory conditions.

    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  5. Mitragynine and its potential blocking effects on specific cardiac potassium channels
    Tay YL, Teah YF, Chong YM, Jamil MFA, Kollert S, Adenan MI, et al.
    Toxicol Appl Pharmacol, 2016 08 15;305:22-39.
    PMID: 27260674 DOI: 10.1016/j.taap.2016.05.022
    Mitragyna speciosa Korth is known for its euphoric properties and is frequently used for recreational purposes. Several poisoning and fatal cases involving mitragynine have been reported but the underlying causes remain unclear. Human ether-a-go-go-related gene (hERG) encodes the cardiac IKr current which is a determinant of the duration of ventricular action potentials and QT interval. On the other hand, IK1, a Kir current mediated by Kir2.1 channel and IKACh, a receptor-activated Kir current mediated by GIRK channel are also known to be important in maintaining the cardiac function. This study investigated the effects of mitragynine on the current, mRNA and protein expression of hERG channel in hERG-transfected HEK293 cells and Xenopus oocytes. The effects on Kir2.1 and GIRK channels currents were also determined in the oocytes. The hERG tail currents following depolarization pulses were inhibited by mitragynine with an IC50 value of 1.62μM and 1.15μM in the transfected cell line and Xenopus oocytes, respectively. The S6 point mutations of Y652A and F656A attenuated the inhibitor effects of mitragynine, indicating that mitragynine interacts with these high affinity drug-binding sites in the hERG channel pore cavity which was consistent with the molecular docking simulation. Interestingly, mitragynine does not affect the hERG expression at the transcriptional level but inhibits the protein expression. Mitragynine is also found to inhibit IKACh current with an IC50 value of 3.32μM but has no significant effects on IK1. Blocking of both hERG and GIRK channels may cause additive cardiotoxicity risks.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  6. Fulltext Mitragynine, an euphoric compound inhibits hERG1a/1b channel current and upregulates the complexation of hERG1a-Hsp90 in HEK293-hERG1a/1b cells
    Tay YL, Amanah A, Adenan MI, Wahab HA, Tan ML
    Sci Rep, 2019 12 24;9(1):19757.
    PMID: 31874991 DOI: 10.1038/s41598-019-56106-6
    Mitragyna speciosa Korth (M. speciosa) has been widely used as a recreational product, however, there are growing concerns on the abuse potentials and toxicity of the plant. Several poisoning and fatal cases involving kratom and mitragynine have been reported but the underlying causes remain unclear. The human ether-a-go-go-related gene 1 (hERG1) encodes the pore-forming subunit underlying cardiac rapidly delayed rectifier potassium current (IKr). Pharmacological blockade of the IKr can cause acquired long QT syndrome, leading to lethal cardiac arrhythmias. This study aims to elucidate the mechanisms of mitragynine-induced inhibition on hERG1a/1b current. Electrophysiology experiments were carried out using Port-a-Patch system. Quantitative RT-PCR, Western blot analysis, immunofluorescence and co-immunoprecipitation methods were used to determine the effects of mitragynine on hERG1a/1b expression and hERG1-cytosolic chaperones interaction. Mitragynine was found to inhibit the IKr current with an IC50 value of 332.70 nM. It causes a significant reduction of the fully-glycosylated (fg) hERG1a protein expression but upregulates both core-glycosylated (cg) expression and hERG1a-Hsp90 complexes, suggesting possible impaired hERG1a trafficking. In conclusion, mitragynine inhibits hERG1a/1b current through direct channel blockade at lower concentration, but at higher concentration, it upregulates the complexation of hERG1a-Hsp90 which may be inhibitory towards channel trafficking.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  7. Quinoline, Indole, and Isogranatanine Alkaloids from Malayan Leuconotis eugeniifolia
    Tan YS, Ng MP, Tan CH, Tang WK, Sim KS, Yong KT, et al.
    J Nat Prod, 2024 Feb 23;87(2):286-296.
    PMID: 38284153 DOI: 10.1021/acs.jnatprod.3c00960
    Nine new alkaloids, eugeniinalines A-H (1-8) and (+)-eburnamenine N-oxide (9), comprising one quinoline, six indole, and two isogranatanine alkaloids, were isolated from the stem-bark extract of the Malayan Leuconotis eugeniifolia. The structures and absolute configurations of these alkaloids were established based on the analysis of the spectroscopic data, GIAO NMR calculations, DP4+ probability analysis, TDDFT-ECD method, and X-ray diffraction analysis. Eugeniinaline A (1) represents a new pentacyclic quinoline alkaloid with a 6/6/5/6/7 ring system. Eugeniinaline G (7) and its seco-derivative, eugeniinaline H (8), were the first isogranatanine alkaloids isolated as natural products. The known alkaloids leucolusine (10) and melokhanine A (11) were found to be the same compound, based on comparison of the spectroscopic data of both compounds, with the absolute configuration of (7R, 20R, 21S). Eugeniinalines A and G (1 and 7) showed cytotoxic activity against the HT-29 cancer cell line with IC50 values of 7.1 and 7.2 μM, respectively.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology
  8. Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa
    Takayama H
    Chem Pharm Bull (Tokyo), 2004 Aug;52(8):916-28.
    PMID: 15304982
    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.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology
  9. Social Functioning of Kratom (Mitragyna speciosa) Users in Malaysia
    Singh D, Müller CP, Vicknasingam BK, Mansor SM
    J Psychoactive Drugs, 2015 5 8;47(2):125-31.
    PMID: 25950592 DOI: 10.1080/02791072.2015.1012610
    Kratom (Mitragyna speciosa) is an indigenous plant known for its traditional medicinal use, and for its addiction potential, in Southeast Asia. In recent years, kratom and its major alkaloid, mitragynine, spread worldwide with largely unknown effects on behavior and mental health. Recent studies show that kratom use can lead to dependence and that mitragynine works as an addictive drug in animal studies. Nevertheless, kratom preparations were also suggested as a less harmful substitute in opiate withdrawal. Potential side-effects of prolonged kratom use, however, are currently unclear. The aim of this study was to investigate the social functioning of regular kratom users in Malaysia. A cross-sectional survey was carried out in three northern states of Peninsular Malaysia investigating 293 regular kratom consumers using the Addiction Severity Index in a snowball sampling technique. Findings showed that regular kratom users do not experience major impairments in their social functioning, despite being dependent on kratom for prolonged periods. Our findings suggest that chronic kratom administration does not significantly impair social functioning of users in a natural context in Malaysia.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  10. Fulltext Antinociceptive action of isolated mitragynine from Mitragyna Speciosa through activation of opioid receptor system
    Shamima AR, Fakurazi S, Hidayat MT, Hairuszah I, Moklas MA, Arulselvan P
    Int J Mol Sci, 2012;13(9):11427-42.
    PMID: 23109863 DOI: 10.3390/ijms130911427
    Cannabinoids and opioids systems share numerous pharmacological properties and antinociception is one of them. Previous findings have shown that mitragynine (MG), a major indole alkaloid found in Mitragyna speciosa (MS) can exert its antinociceptive effects through the opioids system. In the present study, the action of MG was investigated as the antinociceptive agent acting on Cannabinoid receptor type 1 (CB1) and effects on the opioids receptor. The latency time was recorded until the mice showed pain responses such as shaking, licking or jumping and the duration of latency was measured for 2 h at every 15 min interval by hot plate analysis. To investigate the beneficial effects of MG as antinociceptive agent, it was administered intraperitoneally 15 min prior to pain induction with a single dosage (3, 10, 15, 30, and 35 mg/kg b.wt). In this investigation, 35 mg/kg of MG showed significant increase in the latency time and this dosage was used in the antagonist receptor study. The treated groups were administered with AM251 (cannabinoid receptor-1 antagonist), naloxone (non-selective opioid antagonist), naltrindole (δ-opioid antagonist) naloxonazine (μ(1)-receptor antagonist) and norbinaltorpimine (κ-opioid antagonist) respectively, prior to administration of MG (35 mg/kg). The results showed that the antinociceptive effect of MG was not antagonized by AM251; naloxone and naltrindole were effectively blocked; and norbinaltorpimine partially blocked the antinociceptive effect of MG. Naloxonazine did inhibit the effect of MG, but it was not statistically significant. These results demonstrate that CB1 does not directly have a role in the antinociceptive action of MG where the effect was observed with the activation of opioid receptor.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  11. The inhibitory effects of mitragynine on P-glycoprotein in vitro
    Rusli N, Amanah A, Kaur G, Adenan MI, Sulaiman SF, Wahab HA, et al.
    Naunyn Schmiedebergs Arch Pharmacol, 2019 04;392(4):481-496.
    PMID: 30604191 DOI: 10.1007/s00210-018-01605-y
    Mitragynine is a major component isolated from Mitragyna speciosa Korth or kratom, a medicinal plant known for its opiate-like and euphoric properties. Multiple toxicity and fatal cases involving mitragynine or kratom have been reported but the underlying causes remain unclear. P-glycoprotein (P-gp) is a multidrug transporter which modulates the pharmacokinetics of xenobiotics and plays a key role in mediating drug-drug interactions. This study investigated the effects of mitragynine on P-gp transport activity, mRNA, and protein expression in Caco-2 cells using molecular docking, bidirectional assay, RT-qPCR, Western blot analysis, and immunocytochemistry techniques, respectively. Molecular docking simulation revealed that mitragynine interacts with important residues at the nucleotide binding domain (NBD) site of the P-gp structure but not with the residues from the substrate binding site. This was consistent with subsequent experimental work as mitragynine exhibited low permeability across the cell monolayer but inhibited digoxin transport at 10 μM, similar to quinidine. The reduction of P-gp activity in vitro was further contributed by the downregulation of mRNA and protein expression of P-gp. In summary, mitragynine is likely a P-gp inhibitor in vitro but not a substrate. Hence, concurrent administration of mitragynine-containing kratom products with psychoactive drugs which are P-gp substrates may lead to clinically significant toxicity. Further clinical study to prove this point is needed.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  12. Kratom (Mitragyna speciosa): worldwide issues
    Ramanathan S, McCurdy CR
    Curr Opin Psychiatry, 2020 07;33(4):312-318.
    PMID: 32452943 DOI: 10.1097/YCO.0000000000000621
    PURPOSE OF REVIEW: To inform readers about the increasingly popular Western dietary supplement, kratom (Mitragyna speciosa) and how the products are available in the Western world compared with traditional Southeast Asian use. Kratom has been traditionally used for increasing stamina of outdoor laborers (farmers), mood enhancement, pain, and opium addiction. Interestingly, kratom has been reported to have a paradoxical effect in that stimulant feelings, and sedative feelings can be obtained depending on the amount utilized. There are several biologically active alkaloids present in kratom.

    RECENT FINDINGS: Recent studies have been focused on the interactions of mitragynine, the most abundant alkaloid, and opioid-like effects. This has been driven by the harm that kratom products have produced in the Western world, in stark contrast to the lack of harm in Southeast Asian traditional use over centuries. Many users in the Western world ingest kratom for mood enhancement and/or to ween themselves from prescription or illicit opioids. Highly concentrated products and recreational use and misuse have resulted in individuals pushing doses to levels that have not been imagined or ever studied in animal, let alone humans.

    SUMMARY: Kratom, as a preparation and how it is utilized is different around the world.

    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  13. Fulltext Kratom policy: The challenge of balancing therapeutic potential with public safety
    Prozialeck WC, Avery BA, Boyer EW, Grundmann O, Henningfield JE, Kruegel AC, et al.
    Int J Drug Policy, 2019 08;70:70-77.
    PMID: 31103778 DOI: 10.1016/j.drugpo.2019.05.003
    Kratom (Mitragyna speciosa) is a tree-like plant indigenous to Southeast Asia. Its leaves, and the teas brewed from them have long been used by people in that region to stave off fatigue and to manage pain and opioid withdrawal. Evidence suggests kratom is being increasingly used by people in the United States and Europe for the self-management of opioid withdrawal and treatment of pain. Recent studies have confirmed that kratom and its chemical constituents have potentially useful pharmacological actions. However, there have also been increasing numbers of reports of adverse effects resulting from use of kratom products. In August 2016, the US Drug Enforcement Administration announced plans to classify kratom and its mitragynine constituents as Schedule I Controlled Substances, a move that triggered a massive response from pro-kratom advocates. The debate regarding the risks, and benefits and safety of kratom continues to intensify. Kratom proponents tout kratom as a safer and less addictive alternative to opioids for the management of pain and opioid addiction. The anti-kratom faction argues that kratom, itself, is a dangerous and addictive drug that ought to be banned. Given the widespread use of kratom and the extensive media attention it is receiving, it is important for physicians, scientists and policy makers to be knowledgeable about the subject. The purpose of this commentary is to update readers about recent developments and controversies in this rapidly evolving area. All of the authors are engaged in various aspects of kratom research and it is our intention to provide a fair and balanced overview that can form the basis for informed decisions on kratom policy. Our conclusions from these analyses are: (a) User reports and results of preclinical studies in animals strongly suggest that kratom and its main constituent alkaloid, mitragynine may have useful activity in alleviating pain and managing symptoms of opioid withdrawal, even though well-controlled clinical trials have yet to be done. (b) Even though kratom lacks many of the toxicities of classic opioids, there are legitimate concerns about the safety and lack of quality control of purported "kratom" products that are being sold in the US. (c) The issues regarding the safety and efficacy of kratom and its mitragynine constituent can only be resolved by additional research. Classification of the Mitragyna alkaloids as Schedule I controlled substances would substantially impede this important research on kratom.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology
  14. Fulltext Investigation of the Adrenergic and Opioid Binding Affinities, Metabolic Stability, Plasma Protein Binding Properties, and Functional Effects of Selected Indole-Based Kratom Alkaloids
    Obeng S, Kamble SH, Reeves ME, Restrepo LF, Patel A, Behnke M, et al.
    J Med Chem, 2020 01 09;63(1):433-439.
    PMID: 31834797 DOI: 10.1021/acs.jmedchem.9b01465
    Selected indole-based kratom alkaloids were evaluated for their opioid and adrenergic receptor binding and functional effects, in vivo antinociceptive effects, plasma protein binding, and metabolic stability. Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), had higher affinity at opioid receptors than at adrenergic receptors while the vice versa was observed for corynantheidine. The observed polypharmacology of kratom alkaloids may support its utilization to treat opioid use disorder and withdrawal.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  15. Leuconoxine, kopsinitarine, kopsijasmine, and kopsinone derivatives from Kopsia
    Lim SH, Sim KM, Abdullah Z, Hiraku O, Hayashi M, Komiyama K, et al.
    J Nat Prod, 2007 Aug;70(8):1380-3.
    PMID: 17608533
    Four new indole alkaloids were obtained from two Kopsia species, 6-oxoleuconoxine (1) from the leaf extract of K. griffithii and kopsinitarine E (2), kopsijasminine (3), and kopsonoline (4) from the stem-bark extract of K. teoi. The structures of these alkaloids were determined using NMR and MS analysis. Kopsijasminine (3) showed moderate activity in reversing multidrug resistance in vincristine-resistant KB cells.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology
  16. Biologically active vallesamine, strychnan, and rhazinilam alkaloids from Alstonia: Pneumatophorine, a nor-secovallesamine with unusual incorporation of a 3-ethylpyridine moiety
    Lim JL, Sim KS, Yong KT, Loong BJ, Ting KN, Lim SH, et al.
    Phytochemistry, 2015 Sep;117:317-24.
    PMID: 26125941 DOI: 10.1016/j.phytochem.2015.06.024
    Four alkaloids comprising two vallesamine, one strychnan, and one pyranopyridine alkaloid, in addition to 32 other known alkaloids were isolated from two Malayan Alstonia species, Alstonia pneumatophora and Alstonia rostrata. The structures of these alkaloids were determined using NMR and MS analyses, and in one instance, confirmed by X-ray diffraction analysis. The nor-6,7-secovallesamine alkaloid, pneumatophorine, is notable for an unusual incorporation of a 3-ethylpyridine moiety in a monoterpenoid indole. The rhazinilam-type alkaloids (rhazinicine, nor-rhazinicine, rhazinal, and rhazinilam) showed strong cytotoxicity toward human KB, HCT-116, MDA-MB-231, and MRC-5 cells, while pneumatophorine, the uleine alkaloid undulifoline, and the strychnan alkaloids, N4-demethylalstogustine and echitamidine, induced concentration dependent relaxation in phenylephrine-precontracted rat aortic rings.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology
  17. In vitro evaluation of cytochrome P450 induction and the inhibition potential of mitragynine, a stimulant alkaloid
    Lim EL, Seah TC, Koe XF, Wahab HA, Adenan MI, Jamil MF, et al.
    Toxicol In Vitro, 2013 Mar;27(2):812-24.
    PMID: 23274770 DOI: 10.1016/j.tiv.2012.12.014
    CYP450 enzymes are key determinants in drug toxicities, reduced pharmacological effect and adverse drug reactions. Mitragynine, an euphoric compound was evaluated for its effects on the expression of mRNAs encoding CYP1A2, CYP2D6 and CYP3A4 and protein expression and resultant enzymatic activity. The mRNA and protein expression of CYP450 isoforms were carried out using an optimized multiplex qRT-PCR assay and Western blot analysis. CYP1A2 and CYP3A4 enzyme activities were evaluated using P450-Glo™ assays. The effects of mitragynine on human CYP3A4 protein expression were determined using an optimized hCYP3A4-HepG2 cell-based assay. An in silico computational method to predict the binding conformation of mitragynine to the active site of the CYP3A4 enzyme was performed and further validated using in vitro CYP3A4 inhibition assays. Mitragynine was found to induce mRNA and protein expression of CYP1A2. For the highest concentration of 25 μM, induction of mRNA was approximately 70% that of the positive control and was consistent with the increased CYP1A2 enzymatic activity. Thus, mitragynine is a significant in vitro CYP1A2 inducer. However, it appeared to be a weak CYP3A4 inducer at the transcriptional level and a weak CYP3A4 enzyme inhibitor. It is therefore, unlikely to have any significant clinical effects on CYP3A4 activity.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  18. Natural indole butyrylcholinesterase inhibitors from Nauclea officinalis
    Liew SY, Khaw KY, Murugaiyah V, Looi CY, Wong YL, Mustafa MR, et al.
    Phytomedicine, 2015 Jan 15;22(1):45-8.
    PMID: 25636869 DOI: 10.1016/j.phymed.2014.11.003
    Nine monoterpenoid indole alkaloids; naucletine (1), angustidine (2), nauclefine (3), angustine (4), naucline (5), angustoline (6), harmane (7), 3,14-dihydroangustoline (8), strictosamide (9) and one quinoline alkaloid glycoside; pumiloside (10) from Nauclea officinalis were tested for cholinesterase inhibitory activity. All the alkaloids except for pumiloside (10) showed strong to weak BChE inhibitory effect with IC50 values ranging between 1.02-168.55 μM. Angustidine (2), nauclefine (3), angustine (4), angustoline (6) and harmane (7) showed higher BChE inhibiting potency compared to galanthamine. Angustidine (2) was the most potent inhibitor towards both AChE and BChE. Molecular docking (MD) studies showed that angustidine (2) docked deep into the bottom gorge of hBChE and formed hydrogen bonding with Ser 198 and His 438. Kinetic study of angustidine (2) on BChE suggested a mixed inhibition mode with an inhibition constant (Ki) of 6.12 μM.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  19. Alstoscholactine and Alstolaxepine, Monoterpenoid Indole Alkaloids with γ-Lactone-Bridged Cycloheptane and Oxepane Moieties from Alstonia scholaris
    Krishnan P, Lee FK, Chong KW, Mai CW, Muhamad A, Lim SH, et al.
    Org. Lett., 2018 12 21;20(24):8014-8018.
    PMID: 30543301 DOI: 10.1021/acs.orglett.8b03592
    Two new monoterpenoid indole alkaloids, alstoscholactine (1) and alstolaxepine (2), were isolated from Alstonia scholaris. Compound 1 represents a rearranged stemmadenine alkaloid with an unprecedented C-6-C-19 connectivity, whereas compound 2 represents a 6,7- seco-angustilobine B-type alkaloid incorporating a rare γ-lactone-bridged oxepane ring system. Their structures and absolute configurations were determined by spectroscopic analyses. Compound 1 was successfully semisynthesized from 19 E-vallesamine. Compound 2 induced marked vasorelaxation in rat isolated aortic rings precontracted with phenylephrine.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  20. Physicochemical Characterization of Mitragyna speciosa Alkaloid Extract and Mitragynine using In Vitro High Throughput Assays
    Kong WM, Chik Z, Mohamed Z, Alshawsh MA
    Comb Chem High Throughput Screen, 2017;20(9):796-803.
    PMID: 29076424 DOI: 10.2174/1386207320666171026121820
    AIM AND OBJECTIVE: Mitragynine, a major active alkaloid of Mitragyna speciosa, acts as an agonist on µ-opioid receptors, producing effects similar to morphine and other opioids. It has been traditionally utilized to alleviate opiate withdrawal symptoms. Besides consideration about potency and selectivity, a good drug must possess a suitable pharmacokinetic profile, with suitable absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) profile, in order to have a high chance of success in clinical trials.

    MATERIAL AND METHOD: The purity of mitragynine in a Mitragyna speciosa alkaloid extract (MSAE) was determined using Ultra-Fast Liquid Chromatography (UFLC). In vitro high throughput ADMETox studies such as aqueous solubility, plasma protein binding, metabolic stability, permeability and cytotoxicity tests were carried out to analyze the physicochemical properties of MSAE and mitragynine. The UFLC quantification revealed that the purity of mitragynine in the MSAE was 40.9%.

    RESULTS: MSAE and mitragynine are highly soluble in aqueous solution at pH 4.0 but less soluble at pH 7.4. A parallel artificial membrane permeability assay demonstrated that it is extensively absorbed through the semi-permeable membrane at pH 7.4 but very poorly at pH 4.0. Both are relatively highly bound to plasma proteins (> 85 % bound) and are metabolically stable to liver microsomes (> 84 % remained unchanged). In comparison to MSAE, mitragynine showed higher cytotoxicity against WRL 68, HepG2 and Clone 9 hepatocytes after 72 h treatment.

    CONCLUSION: The obtained ADME and cytotoxicity data demonstrated that both MSAE and mitragynine have poor bioavailability and have the potential to be significantly cytotoxic.

    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
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