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PubMed1998

Creating a functional opioid alkaloid binding site in the orphanin FQ receptor through site-directed mutagenesis.

Although much has been learned about the mechanisms of ligand selectivity between different opioid receptor subtypes, little is known about the common opioid binding pocket shared by all opioid receptors. The recently discovered orphanin system offers a good opportunity to study the mechanisms involved in the binding of opioid versus nonopioid ligands. In the current study, we adopt a "gain of function" approach aimed at shifting the binding profile of the orphanin FQ receptor toward that of the opioid receptors. After two rounds of mutagenesis, several orphanin FQ receptor mutants can be labeled with the opiate alkaloid [3H]naltrindole and show greatly increased affinities toward the opiate antagonists naltrexone, nor-binaltrophine HCl, and (-)-bremazocine. These orphanin FQ receptor mutants also display stereospecificity similar to that of opioid receptors. Furthermore, the orphanin FQ receptor mutant that has the best affinities toward the opioid alkaloids shows, in the presence of GTP and high salt concentration, an affinity-shift profile similar to that of the delta receptor. Most strikingly, the same mutant exhibits naltrindole-sensitive etorphine-stimulated [35S]guanosine-5'-O-(3-thio)triphosphate binding, whereas the effect of etorphine on GTP binding cannot be inhibited by naltrindole in the wild-type receptor. Our results indicate that 1) several residues in the orphanin FQ receptor are critical to its selectivity against the opiate alkaloids, particularly antagonists; and 2) mutating these residues to those of the opioid receptor at the corresponding position preserves the agonist/antagonist nature of opiate alkaloids as they interact with the mutant receptor. It is reasonable to hypothesize that the corresponding residues in the opioid receptors may form a functional common binding pocket for opiate alkaloids. These findings may be helpful to medicinal chemists in designing ligands for the orphanin FQ receptor based on the structure of the opiate alkaloids.

Amino Acid Substitution↗

PubMed1992

Accumulation of Ergopeptide Alkaloids in Symbiotic Tall Fescue Grown under Deficits of Soil Water and Nitrogen Fertilizer.

The fungus Acremonium coenophialum is endophytically associated with tall fescue (Festuca arundinacea Schreber). Within this symbiotum the fungus produces ergopeptide alkaloids, which are associated with livestock toxicoses. Environmental effects on the production of ergot alkaloids within the symbiotum are unknown. We conducted a greenhouse study of the effects of flooding, nitrogen rate during fertilization (11, 73, and 220 mg of N per pot weekly), nitrogen form (3.4 and 34 mg of N as NH(4) or NO(3) per pot), and drought stress (-0.03, -0.05, and -0.50 MPa) on ergopeptide alkaloid concentrations in one genotype of nonsymbiotic and symbiotic tall fescue grown in plastic pots. It was determined that the concentration of ergovaline, the major type of ergopeptide alkaloid, was increased but was not as high as that in nonflooded controls. Total ergopeptide and ergovaline concentrations in plants receiving high (220 mg of N per pot) and low (11 mg of N per pot) levels of NH(4)NO(3) fertilization were not affected by flooding. The form of nitrogen was important since all concentrations of NO(3)-N increased ergopeptide alkaloid content, as opposed to the effects of NH(4)-N, which was effective only at high concentrations (34 mg of N per pot). Ergopeptide concentrations were highest in drought-stressed plants grown at -0.50 MPa and fertilized at the moderate or high N rate. The results suggest that within this genotype, ergopeptide alkaloid biosynthesis by the fungus is not appreciably affected by flooding but is greatly increased by high rates of N fertilization and moderate water deficit.

Journal Article↗

PubMed1980

The mode of action of Vinca alkaloids.

P388 leukemia-bearing mice were given a single i.p. injection of [14C]-vincristine and the levels of radioactivity in the tumors and host tissues were determined as a function of time. The highest levels of radioactivity were found in the gallbladder followed by the tumor, spleen and liver, respectively. 24 h after drug administration the tumor contains 5.8% of the radioactivity detected in the tumor 1 h after drug administration. The tumor thus does not retain the alkaloid for a long period of time. At subcellular level tubulin was found to bind the highest amount of the alkaloid, followed by the fraction containing Golgi and plasma membranes. P388 tumor sensitive to vincristine (VCR) and formyl-leurosine (F-leu) incorporates three times more VCR and four times more F-leu than the resistant line of the same tumor. The different drug uptake as well as the different Vinca alkaloid binding capacity of membrane fractions of the sensitive and resistant P388 leukemias suggests that the composition and/or the structure of the cell membrane has changed in the resistant line. Vinca alkaloid-induced cell cycle changes were evaluated by cytophotometry. The cytotoxic effect of Vinca alkaloids does not correlate with their ability to arrest cells in metaphase. Multinuclear cells showing higher policy could be detected in the later phase of the treatment; these cells are the representatives of the surviving population. Selective killing of G1 cells is supposed to be a possible way of the cytotoxic action of Vinca alkaloids.

Animals↗

PubMedDate not supplied

Antagonistic effects of simultaneous exposure of ergot alkaloids on kidney adenosine triphosphatase system.

Much of the research on fescue toxicosis has concentrated on evaluating animal response to grazing endophyte-infected (E+) versus endophyte-free tall fescue or the effects of single toxins such as ergonovine (EN), ergovaline (EV), or ergotamine (ET) on animal performance. Such approaches have eliminated the opportunity to test the possible additive, synergistic, or antagonistic interactions of one or more ergot alkaloids with the other ergot alkaloids found in E+ tall fescue. This study was conducted to determine the effects of simultaneous exposure of pairs of EN, EV, and ET on the kidney adenosine triphosphatase (ATPase) system in vitro. Tests were performed using three separate rat kidney homogenates and were repeated four times at concentrations of 0, 75, and 200 microM. Individually, EN, EV, and ET induced dose-dependent inhibitions of kidney Na(+)/K(+) ATPase, with EN being most potent, followed by purified EV, and then by ET. The ergot alkaloids inhibited Mg(2+) ATPase to a lesser degree than Na(+)/K(+) ATPase, with EN again being the most potent toxin. Simultaneous exposure to any combination of the ergot alkaloid pairs tested (EV + ET, EV + EN, and ET + EN) resulted in significant interactions (P < 0.05), indicating antagonistic effects on the inhibition of Na(+)/K(+) ATPase and Mg(2+) ATPase for most concentration combinations. These interactions suggest that in studies of the effects of any ergot alkaloid on animal performance, effects of other ergot alkaloids may also be present. Effects may not be additive, as was the case in this study, and the presence of one toxin may enhance or hinder the effectiveness of others.

Animals↗

PubMed2002

Urinary excretion of ipecac alkaloids in human volunteers.

Limited data are available regarding urinary excretion of ipecac alkaloids in humans. In this study, ipecac syrup was administered po to 12 healthy human volunteers at a dose of either 20 mL or 30 mL, and urinary excretions of cephaeline and emetine as well as blood and vomit concentrations were detected by HPLC. All participants showed vomiting after the 30 mL dose within 1 h, whereas 2/6 did not show vomiting within 4 h after the 20 mL dose. Percentage recovery of alkaloids in vomit were 39 +/- 38 or 76 +/- 14% after the 20 mL or 30 mL doses, respectively. In most participants, plasma alkaloids reached their maximum levels within I h and became undetectable after 6 h. Total excretions of ipecac alkaloids into the urine within the first 48 h were less than 2%, but both alkaloids were detectable in the urine at 2w in all participants and could be detected up to 12w in 1/2 participants who did not vomit. These results show that ipecac alkaloids may be detectable in urine several weeks after ingestion and suggest that their detection in urine may be helpful to identify the Munchausen syndrome by proxy using ipecac syrup.

Administration, Oral↗

PubMed1989

[Studies on the chemical constituents of Fritillaria in Hubei. X. Isolation and identification of alkaloids from Fritillaria ebeiensis var.purpurea G.D.Yu et P.Li].

The bulb of Fritillaria ebeiensis var. purpurea G.D. Yu et P. Li (Liliaceae) are commercially available as the substitute for the principal Chinese traditional medicine "Beimu". This plant is easily cultivated, has high alkaloid content and conspicuous antitussive and expectorant effects. Seven C-nor-D-homo steroidal alkaloids (I-VII) were isolated from the bulb cultivated in Suizhou district, Hubei. I-IV have been identified as the known alkaloids peimine, peiminine, ebeinine and ebeinone on the basis of spectral data and by TLC and mixed mp comparison with authentic samples. The alkaloid VI, C27H43NO2, mp 186-188 degrees C, named ziebeimine, is a new alkaloid isolated from the title plant. The structure of VI has been established as 5 alpha, 14 alpha-cevanine-13, 17-dehydro-3 alpha, 6 beta-diol on the basis of its IR, 1H-NMR, 13C-NMR and mass spectra. The structure of alkaloids V and VII is still under investigation.

Cevanes↗

PubMed1990

Determination of Senecio alkaloids by thermospray liquid chromatography/mass spectrometry.

A series of Senecio alkaloid and alkaloid N-oxide standards has been analyzed using positive and negative ion thermospray liquid chromatography/mass spectrometry (LC/MS) with an ammonium acetate-containing mobile phase. On-line separations of pyrrolizidine alkaloids from extracts of Senecio jacobaea (tansy ragwort) and Senecio vulgaris (common groundsel) were done using an ammonium hydroxide-containing mobile phase. All of the alkaloids known to be present in the extracts were detected by ammonium hydroxide thermospray LC/MS, as well as many other components which may be as-yet-unidentified alkaloids.

Acetates↗

PubMed1985

Enzyme inhibition. VIII: Mode of inhibition of reverse transcriptase activity by analogues, isomers, and related alkaloids of coralyne.

Coralyne analogues, isomers, and related alkaloids were examined as inhibitors of reverse transcriptase of RNA tumor viruses in the presence of polyriboadenylic acid-oligodeoxythymidylic acid (Poly rA.oligo dT), polydeoxyadenylic acid-oligodeoxythymidylic acid (Poly dA.oligo dT), polyribocytidylic acid-oligodeoxyguanylic acid (Poly rC.oligo dG), activated calf thymus DNA, and 70S RNA template primers. The inhibition of the reverse transcriptase exhibited by analogues, isomers, and related alkaloids of coralyne was due to the interaction of the alkaloids with the template primers and was competitive. Furthermore, the addition of the alkaloids stopped instantly the DNA polymerization processes. Comparison of the inhibition of reverse transcriptase, antileukemic activities exhibited by the alkaloids, and the structure-activity relationships have been published elsewhere.

Alkaloids↗

PubMed2007

Molecular aspects on the interaction of protoberberine, benzophenanthridine, and aristolochia group of alkaloids with nucleic acid structures and biological perspectives.

Alkaloids occupy an important position in chemistry and pharmacology. Among the various alkaloids, berberine and coralyne of the protoberberine group, sanguinarine of the benzophenanthridine group, and aristololactam-beta-d-glucoside of the aristolochia group have potential to form molecular complexes with nucleic acid structures and have attracted recent attention for their prospective clinical and pharmacological utility. This review highlights (i) the physicochemical properties of these alkaloids under various environmental conditions, (ii) the structure and functional aspects of various forms of deoxyribonucleic acid (DNA) (B-form, Z-form, H(L)-form, protonated form, and triple helical form) and ribonucleic acid (RNA) (A-form, protonated form, and triple helical form), and (iii) the interaction of these alkaloids with various polymorphic DNA and RNA structures reported by several research groups employing various analytical techniques like absorbance, fluorescence, circular dichroism, and NMR spectroscopy; electrospray ionization mass spectrometry, thermal melting, viscosity, and DNase footprinting as well as molecular modeling and thermodynamic studies to provide detailed binding mechanism at the molecular level for structure-activity relationship. Nucleic acids binding properties of these alkaloids are interpreted in relation to their biological activity.

Alkaloids↗

PubMed2005

Do naïve ruminants degrade alkaloids in the rumen?

Three different methods for the culture of rumen microorganisms (Hungate's technique, the Hohenheim in vitro gas production method, and the semicontinuous rumen simulation technique) were employed to study the influence of various alkaloids (sparteine, lupanine, cytisine, atropine, quinidine, lobeline, harmaline, arecoline, nicotine, caffeine, pilocarpine, gramine, senecionine, and monocrotaline) on rumen microorganisms. Rumen micro-organisms from naive ruminants (sheep, cattle) that had not been exposed to the alkaloids before were generally not able to degrade most of the alkaloids. Only the alkaloids pilocarpine, gramine, and monocrotaline appeared to be degradable. Rumen microorganisms from a sheep preconditioned to lupin alkaloids tolerated lupanine much better than nonadapted microorganisms, but no degradation occurred. The findings indicate that the main site of detoxification in naive ruminants is not the rumen but more likely the liver and kidneys as in nonruminants.

Alkaloids↗

PubMed1993

Detection of alkaloids in foods with a multi-detector high-performance liquid chromatographic system.

A general screening method for alkaloid drugs in foods is described based on high-performance liquid chromatography with ultraviolet detection at three wavelengths, followed by fluorescence and electrochemical detectors in series. The chromatographic conditions include an ion-pairing reagent, which makes it possible to chromatograph acidic and basic drugs with one screen. Relative response ratios were determined from the peak areas of the alkaloids on the basis of all the detector signals. These ratios were used to create a "fingerprint" of the drugs and to predict the identity of an unknown component in a sample matrix. The fluorescence and electrochemical detectors allowed a detection limit for many of the alkaloids which would not be attainable with the ultraviolet detector alone. Typical detection limits with the electrochemical detector were 5-50 ng/ml and with the fluorescence detector 5-500 ng/ml, while the ultraviolet detector had detection limits of 1-20 micrograms/ml. The spiking concentrations in the relative response ratio experiments were approximately five times above the lowest detection limit. The extraction method investigated for orange juice yielded recoveries for most alkaloids of 80-100%. A stability study of ergot alkaloids in various food matrices demonstrated degradation, depending on the matrix, temperature, and duration of the experiment.

Alkaloids↗

PubMed2000

Cytotoxicity and cell cycle effects of the plant alkaloids cryptolepine and neocryptolepine: relation to drug-induced apoptosis.

Cryptolepine and neocryptolepine are two indoloquinoline derivatives isolated from the roots of the african plant Cryptolepis sanguinolenta. These two alkaloids, which only differ by the respective orientation of their indole and quinoline rings, display potent cytotoxic activities against tumour cells and present antibacterial and antiparasitic properties. Our previous molecular studies indicated that these two natural products intercalate into DNA and interfere with the catalytic activity of human topoisomerase II. Here we have extended the study of their mechanism of action at the cellular level. Murine and human leukemia cells were used to evaluate the cytotoxicity of the drugs and their effects on the cell cycle were measured by flow cytometry. Cryptolepine, and to a lesser extent neocryptolepine, provoke a massive accumulation of P388 murine leukemia cells in the G2/M phase. With HL-60 human leukemia cells, the treatment with cryptolepine leads to the appearance of a hypo-diploid DNA content peak (sub-G1) characteristic of the apoptotic cell population. With both P388 and HL-60 cells, cryptolepine proved about four times more toxic than its isomer. But the use of the HL-60/MX2 cell line resistant to the anticancer drug mitoxantrone suggests that topoisomerase II may not represent the essential cellular target for the alkaloids, which are both only two times less toxic to the resistant HL-60/MX2 cells compared to the parental cells. The capacity of the drugs to induce apoptosis of HL-60 human leukemia cells was examined by complementary biochemical techniques. Western blotting analysis revealed that cryptolepine, but not neocryptolepine, induces cleavage of poly(ADP-ribose) polymerase but both alkaloids induce the release of cytochrome c from the mitochondria. The cleavage of poly(ADP-ribose) polymerase observed with cryptolepine correlates with the appearance of a marked sub-G1 peak in the cell cycle experiments. The proteolytic activity of Asp-Glu-Val-Asp- or Ile-Glu-Thr-Asp-caspases was found to be enhanced much more strongly with cryptolepine than with its isomer, as expected from their different cytotoxic potential. Despite the activation of the caspase cascade, we did not detect internucleosomal cleavage of DNA in the HL-60 cells treated with the alkaloids. Altogether, the results shed light on the mechanism of action of these two plant alkaloids.

Alkaloids↗

PubMed1993

Strictosidine: from alkaloid to enzyme to gene.

In this review, the elucidation of the structure of the first key alkaloidal intermediate in monoterpenoid indole alkaloid biosynthesis, 3 alpha(S)-strictosidine, is presented. The discovery of the enzyme which catalyses the stereospecific formation of this alkaloidal precursor from tryptamine and secologanin, strictosidine synthase, is also detailed. From the knowledge provided by the stereochemical structure of strictosidine and the biochemical characteristics of the biosynthetic enzyme, strictosidine synthase, a new approach to the study of monoterpenoid indole alkaloid biosynthesis was developed. Physiological studies of monoterpenoid indole alkaloid biosynthesis at the enzymic level in plants and plant cell cultures were performed followed by the analyses of these systems at the level of molecular genetics.

Amino Acid Sequence↗

PubMed2003

In vivo monitoring of alkaloid metabolism in hybrid plant cell cultures by 2D cryo-NMR without labelling.

Non-invasive measurements of alkaloid metabolism in plant cell suspension cultures of a somatic hybrid from Rauvolfia serpentina Benth. ex Kurz and Rhazya stricta Decaisne were carried out. When cell samples were taken sequentially from a stock feeding experiment, measuring times for in vivo NMR of 40 min were sufficient for following conversions of alkaloids at the natural abundance of 13C. Degradation of ajmaline added to the cells at 1.6 mM concentration to raumacline could be monitored after 96 h on a standard 800 MHz NMR instrument (Avance 800). Feeding vinorine an intermediate of ajmaline biosynthesis at 1.8 mM showed with a 500 MHz CryoProbe that the alkaloid enters two metabolic routes. Vinorine is intracellularly transformed on route I through vellosimine and 10-deoxysarpagine into sarpagine. On route II, the alkaloid is converted by hydroxylation through vomilenine into the glucoside raucaffricine. Intracellular alkaloid concentrations of approximately 500 microM are measurable in vivo with cryogenic NMR technology.

Ajmaline↗

PubMed2006

Terpenoid indole alkaloids from Winchia calophylla.

Three new indole alkaloids, N(4)-demethyl-12-methoxyalstogustine (1), 17-carboxyl-N(4)-methylechitamidine chloride (2), and 17-carboxyl-12-methoxy-N(4)-methylechitamidine chloride (3), along with 15 known alkaloids, were isolated from the ethanolic extract of the stem bark of Winchia calophylla. The structures of 1-3 were elucidated on the basis of spectroscopic means and chemical methods. The determination of relative configurations at C-19 and C-20 for 1-3 was aided by 13C NMR spectroscopic data. The absolute configurations of alkaloids 1-3 were determined by direct comparison of their CD spectra with those of known alkaloids. All the alkaloids were tested in cytotoxic assays against P-388 and A-549 tumor cell lines, and only two of them showed weak activity against the A-549 cell line.

Animals↗

PubMed2006

Post-genome research on the biosynthesis of ergot alkaloids.

Genome sequencing provides new opportunities and challenges for identifying genes for the biosynthesis of secondary metabolites. A putative biosynthetic gene cluster of fumigaclavine C, an ergot alkaloid of the clavine type, was identified in the genome sequence of ASPERGILLUS FUMIGATUS by a bioinformatic approach. This cluster spans 22 kb of genomic DNA and comprises at least 11 open reading frames (ORFs). Seven of them are orthologous to genes from the biosynthetic gene cluster of ergot alkaloids in CLAVICEPS PURPUREA. Experimental evidence of the identified cluster was provided by heterologous expression and biochemical characterization of two ORFs, FgaPT1 and FgaPT2, in the cluster of A. FUMIGATUS, which show remarkable similarities to dimethylallyltryptophan synthase from C. PURPUREA and function as prenyltransferases. FgaPT2 converts L-tryptophan to dimethylallyltryptophan and thereby catalyzes the first step of ergot alkaloid biosynthesis, whilst FgaPT1 catalyzes the last step of the fumigaclavine C biosynthesis, i. e., the prenylation of fumigaclavine A at C-2 position of the indole nucleus. In addition to information obtained from the gene cluster of ergot alkaloids from C. PURPUREA, the identification of the biosynthetic gene cluster of fumigaclavine C in A. FUMIGATUS opens an alternative way to study the biosynthesis of ergot alkaloids in fungi.

Aspergillus fumigatus↗

PubMed2025

Transcriptome and metabolome profiling of the medicinal plant Dictamnus dasycarpus reveal key genes involved in quinoline alkaloids biosynthesis and limonoids biosynthesis.

BACKGROUND: As a member of Rutaceae family, Dictamnus dasycarpus Turcz. represents a prominent medicinal plant and economically valuable crop in traditional Chinese medicine, and is renowned for its therapeutic efficacy in treating dermatological conditions. The pharmacological activity of this species primarily stems from quinoline alkaloids and limonoids, which predominantly accumulate in the taproots. These bioactive compounds serve as critical determinants of both medicinal quality and crop yield. Nevertheless, the molecular mechanisms governing their dynamic accumulation patterns in D. dasycarpus taproots remain uncertain, and the fundamental biochemical basis underlying this process has yet to be elucidated. RESULTS: Metabolomic and transcriptomic analyses were carried out to investigate metabolites and gene expression during the development of D. dasycarpus taproots. The differentially accumulated secondary metabolites (DAMs) mainly included quinoline alkaloids and limonoids, and the accumulation of total alkaloids and total limonoids primarily occurred during 2- and 4-year-old. The differentially expressed genes (DEGs) are related to Glycolysis/Gluconeogenesis, Phenylalanine, tyrosine and tryptophan biosynthesis, Tryptophan metabolism, Terpenoid backbone biosynthesis, Sesquiterpenoid and triterpenoid biosynthesis, which had a close relationship with the accumulation of quinoline alkaloids and limonoids. Furthermore, we identified that some CYP450s, acetyltransferase, isomerase, 2-ODDs and others may play an important role in the process of producing quinoline alkaloids and limonoids. CONCLUSION: These results elucidated the molecular mechanisms and metabolic changes underlying the dynamic accumulation process occurring in the taproots of D. dasycarpus. These findings provide a theoretical basis for the planting and harvesting of D. dasycarpus.

Limonins↗

PubMed2001

[Inhibition effect of Amaryllidaceae alkaloids, lycorine and lycoricidinol on macrophage TNF-alpha production].

We previously demonstrated that Amaryllidaceae alkaloids, lycorine and lycoricidinol, inhibit induction of apoptosis by calprotectin derived from neutrophils, and that the latter alkaloid showed suppression in rat adjuvant-induced arthritis model. These findings suggest that the alkaloids have a modulating activity against inflammatory reaction. To explore further the mechanism of the suppression for inflammation, we studied the effect of the alkaloids on macrophage tumor necrosis factor (TNF-alpha) production in vitro, since TNF-alpha is recognized as a pivotal cytokine to regulate inflammation. As a result of this study, lycorine and lycoricidinol inhibited TNF-alpha production of murine macrophages stimulated with lipopolysaccharide (ID50 were 0.2 microgram/ml and 0.002 microgram/ml, respectively). The inhibition was also observed in macrophages treated by Gram-positive bacteria, Enterococcus faecalis. Both lycorine and lycoricidinol reportedly have inhibitory activity for protein biosynthesis. Although the inhibition of TNF-alpha production by lycoricidinol was mainly due to the inhibition of protein biosynthesis, lycorine showed inhibition against TNF-alpha production at lower concentrations than the case that they inhibited 35S-Cysteine/35S-Methionine incorporation into macrophages. These facts suggest that the inhibition of TNF-alpha production is not due to the inhibitory activity against protein translation at least at lower concentrations. From these results, it was concluded that these alkaloids exert inhibitory effects not only on neutrophil apoptosis-inducing protein, calprotectin, but also on macrophage TNF-alpha production.

Alkaloids↗