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Gunars Duburs - One of the best experts on this subject based on the ideXlab platform.

  • use of pyridinium ionic liquids as catalysts for the synthesis of 3 5 bis dodecyloxycarbonyl 1 4 Dihydropyridine Derivative
    Central European Journal of Chemistry, 2011
    Co-Authors: Karlis Pajuste, Gunars Duburs, Aiva Plotniece, Kintija Kore, Liva Intenberga, Brigita Cekavicus, Dainis Kaldre, Arkadij Sobolev
    Abstract:

    The synthesis of cationic amphiphilic 1,4-Dihydropyridine Derivative, potential gene delivery agent is achieved via an efficient multi-step sequence. The key step of this approach is a two-component Hantzsch type cyclisation of 3-oxo-2-[1-phenylmethylidene]-butyric acid dodecyl ester and 3-amino-but-2-enoic acid dodecyl ester utilising bis(2-hydroxyethyl)ether as a solvent and 1-butyl-4-methylpyridinium chloride as a catalyst. The 1,4-Dihydropyridine Derivative with long alkyl ester chains at positions 3 and 5 of the 1,4-DHP ring — 3,5-bis(dodecyloxycarbonyl)-2,6-dimethyl-4-phenyl-1,4-Dihydropyridine was obtained in substantially higher yield with respect to classical Hantzsch synthesis. Bromination of this compound followed by nucleophilic substitution of bromine with pyridine gave the desired cationic amphiphilic 1,4-Dihydropyridine. Open image in new window

  • A 1,4-Dihydropyridine Derivative reduces DNA damage and stimulates DNA repair in human cells in vitro
    2005
    Co-Authors: Nadezhda I Ryabokon, Gunars Duburs, Rose I Goncharova, Joanna Rzeszowska-wolny
    Abstract:

    Abstract Compounds of the 1,4-Dihydropyridine (1,4-DHP) series have been shown to reduce spontaneous, alkylation-and radiationinduced mutation rates in animal test systems. Here we report studies using AV-153, the 1,4-DHP Derivative that showed the highest antimutagenic activity in those tests, to examine if it modulates DNA repair in human peripheral blood lymphocytes and in two human lymphoblastoid cell lines, Raji and HL-60. AV-153 caused a 50% inhibition of growth (IC 50 ) of Raji and HL-60 cells at 14.9 ± 1.2 and 10.3 ± 0.8 mM, respectively, but did not show a cytotoxic effect at concentrations <100 M. Alkaline single-cell gel electrophoresis (comet) assays showed that AV-153 reduced the number of DNA strand breaks in untreated cells and also in cells exposed to 2 Gy of gamma-radiation, 100 M ethylmethane sulfonate (EMS), or 100 M H 2 O 2 . DNA damage was reduced by up to 87% at AV-153 concentrations between 1 and 10 nM, and a positive dose-effect relationship was seen between 0.01 and 1 nM. Comparison of the kinetics of DNA strand-break rejoining in the presence and absence of AV-153 revealed a considerable influence on the rate of repair. In view of the resemblance of this compound's structure to that of dihydronicotinamide, a substrate for poly(ADP-rybose)polymerase, the modulation of DNA repair by AV-153 could involve an influence on poly(ADP)ribosylation

  • effect of cerebrocrast on the lymphocyte blast transformation activity in normal and streptozotocin induced diabetic rats
    Cell Biochemistry and Function, 1999
    Co-Authors: Janĩna Briede, Daina Daija, Mara Stivrina, Gunars Duburs
    Abstract:

    Both IDDM and NIDDM are characterized by deviations in peripheral T and B lymphocyte count, Thelper: Tsuppressor ratio, as well as by impaired Tsuppressor function. These abnormalities may promote insulin antibody and other antibody production, contributing to overt diabetes mellitus development in early stage of the disease. In the present study we explored the effects of cerebrocrast(1, 4-Dihydropyridine Derivative) administration on Con A- and IL-2-stimulated tissue lymphocyte blast transformation activity and on the thymus and lymph node mass in normal and streptozotocin (STZ)-induced diabetic rats. It was established that cerebrocrast, administered four times at the doses of 0.05 and 0.5 mg kg-1, has long-term (up to 14 days) effects on the immune system and protects against the toxic effect of STZ in STZ-induced diabetic rats, preventing thymus and lymph node mass loss. We conclude that cerebrocrast administration leads to the increase in number and activity of Thelper and Tsuppressor lymphocytes. Glycolysis and DNA synthesis in these cells is augmented under the influence of cerebrocrast administration. We propose that the increase in lymphocyte suppressive activity caused by cerebrocrast administration may prevent the development of IDDM and NIDDM in patients with pre-diabetes, but in patients with early and overt diabetes mellitus the drug administration may prevent the overexpression of insulin antibodies and other antibodies. The effect of cerebrocrast on the de novo production of insulin and IL-2 receptors may be beneficial for IDDM and NIDDM patients.

Tetsuo Satoh - One of the best experts on this subject based on the ideXlab platform.

  • gsh independent denitration of the nitrate ester of a Dihydropyridine Derivative in rabbit hepatic cytosol
    Biochemical Pharmacology, 1995
    Co-Authors: Naoyoshi Ogawa, Takuya Hirose, Kiyomi Fukushima, Toshio Suwa, Tetsuo Satoh
    Abstract:

    The denitration of a Dihydropyridine Derivative having two nitrate ester groups, 2-nitrooxypropyl 3-nitrooxypropyl 1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridinedicarboxylate (NND), by rabbit hepatic cytosol was investigated. Sephadex G-150 chromatography of ammonium sulfate precipitate (30–60%) from the cytosol demonstrated the presence of two distinct activities (peak I and peak II) responsible for denitration of [14C]-NND. The first peak, peak I, was observed in the presence of dithiothreitol (DTT), but not in the presence of glutathione (GSH). Moreover, the denitration activity of peak I was not inhibited by S-hexyl GSH, an inhibitor of GSH S-transferase (GST), indicating that peak I possessed no GST activity. In contrast, the denitration activity of peak II, having GST activity, required GSH and was inhibited by S-hexyl GSH. These results strongly suggest that the GSH-independent enzyme system(s), in addition to GST, is responsible for denitration of nitrate esters of NND.

  • metabolism of a nitrate ester Dihydropyridine Derivative in rabbit hepatic microsomes and cytosol
    Xenobiotica, 1995
    Co-Authors: Naoyoshi Ogawa, Takuya Hirose, Kiyomi Fukushima, Toshio Suwa, Tetsuo Satoh
    Abstract:

    1. The metabolism of a nitrate ester-substituted Dihydropyridine Derivative (NND) in vitro was characterized with rabbit hepatic microsomes and cytosol.2. Denitration activity was located in both the microsomal and cytosolic fractions, whereas oxidation to the pyridine analogue was solely located in the microsomal fraction.3. Oxidation to the pyridine analogue required NADPH and was inhibited by carbon monoxide, miconazole and SKF-525A, suggesting that oxidation was catalysed by P450.4. Denitration activity in the microsomes required either NADPH or GSH. Together with these results, responses to various inhibitors indicate participation of both P450 and glutathione S-transferase (GST).5. Denitration activity in cytosol was activated by glutathione (GSH), and by dithiothreitol (DTT) to a greater extent. GSH-dependent denitration was inhibited by S-hexyl GSH, an inhibitor of GST, but DTT-dependent denitration was not. Moreover, the formation patterns of the mono-denitrated metabolites, M1 and M2 were shown ...

Michael J. Iadarola - One of the best experts on this subject based on the ideXlab platform.

  • small molecule positive allosteric modulation of trpv1 activation by vanilloids and acidic ph
    Journal of Pharmacology and Experimental Therapeutics, 2012
    Co-Authors: Krisztián Kaszás, Jason M Keller, Claudio Coddou, Santosh K Mishra, Mark A Hoon, Stanko S Stojilkovic, Kenneth A Jacobson, Michael J. Iadarola
    Abstract:

    Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a high-conductance, nonselective cation channel strongly expressed in nociceptive primary afferent neurons of the peripheral nervous system and functions as a multimodal nociceptor gated by temperatures greater than 43°C, protons, and small-molecule vanilloid ligands such as capsaicin. The ability to respond to heat, low pH, vanilloids, and endovanilloids and altered sensitivity and expression in experimental inflammatory and neuropathic pain models made TRPV1 a major target for the development of novel, nonopioid analgesics and resulted in the discovery of potent antagonists. In human clinical trials, observations of hyperthermia and the potential for thermal damage by suppressing the ability to sense noxious heat suggested that full-scale blockade of TRPV1 function can be counterproductive and subtler pharmacological approaches are necessary. Here we show that the Dihydropyridine Derivative 4,5-diethyl-3-(2-methoxyethylthio)-2-methyl-6-phenyl-1,4-(±)-Dihydropyridine-3,5-dicarboxylate (MRS1477) behaves as a positive allosteric modulator of both proton and vanilloid activation of TRPV1. Under inflammatory-mimetic conditions of low pH (6.0) and protein kinase C phosphorylation, addition of MRS1477 further increased sensitivity of already sensitized TPRV1 toward capsaicin. MRS1477 does not affect inhibition by capsazepine or ruthenium red and remains effective in potentiating activation by pH in the presence of an orthosteric vanilloid antagonist. These results indicate a distinct site on TRPV1 for positive allosteric modulation that may bind endogenous compounds or novel pharmacological agents. Positive modulation of TRPV1 sensitivity suggests that it may be possible to produce a selective analgesia through calcium overload restricted to highly active nociceptive nerve endings at sites of tissue damage and inflammation.

Yasushi Abiko - One of the best experts on this subject based on the ideXlab platform.

  • effect of efonidipine a novel Dihydropyridine Derivative on myocardial metabolic changes induced by coronary artery ligation in dogs comparison with nifedipine
    Fundamental & Clinical Pharmacology, 1997
    Co-Authors: T Yokoyama, K Ichihara, Yasushi Abiko
    Abstract:

    Summary— Efonidipine is a Dihydropyridine Derivative having a vasodilating action, which is slower in onset and longer in duration than that of nifedipine. In the present study, we compared the effects of efonidipine with those of nifedipine on the ischemic myocardial metabolism in anesthetized dogs. The heart was made ischemic by ligating the left anterior descending coronary artery (LAD) completely for 3 or 30 min. Efonidipine or nifedipine was injected intravenously, 10 or 3 min, respectively, before the start of LAD occlusion. Efonidipine (0.01 or 0.03 mg/kg) decreased both blood pressure and heart rate, whereas nifedipine (0.003 mg/kg) decreased blood pressure and increased heart rate. The magnitude of decrease in mean blood pressure induced by 0.03 mg/kg efonidipine was similar to that induced by 0.003 mg/kg nifedipine. Although efonidipine did not modify the changes in myocardial carbohydrate metabolism induced by ischemia, it attenuated the ischemia-induced decrease in the myocardial level of adenosine triphosphate and energy charge potential. Nifedipine, however, did not modify the changes in both myocardial energy and carbohydrate metabolism induced by ischemia. The results suggest that efonidipine has a cardioprotective effect in the dog, probably because of its negative chronotropic effect.

  • efonidipine a long acting Dihydropyridine Derivative attenuates coronary vasoconstriction induced by endothelin 1 in dogs
    Japanese Journal of Pharmacology, 1996
    Co-Authors: T Yokoyama, K Ichihara, Yasushi Abiko
    Abstract:

    Effect of efonidipine, a long-acting Dihydropyridine Derivative, on the endothelin-1 (ET-1)-induced coronary vasoconstriction was studied in open-chest anesthetized dogs. Efonidipine (0.03 or 0.1 mg/kg) was administered i.v. 10 min before an intracoronary injection of ET-1 (30 pmol/kg). An intracoronary injection of ET-1 decreased coronary blood flow (CBF) that was measured by a flow probe. The ET-1-induced decrease in CBF was sustained for more than 30 min without significant changes in blood pressure and heart rate. Pretreatment with efonidipine attenuated the decrease in CBF induced by ET-1 significantly and dose-dependently. ET-1 also reduced coronary diameter for more than 30 min as evaluated by the coronary angiography technique. Pretreatment with efonidipine also attenuated the reduction in coronary diameter induced by ET-1 significantly and dose-dependently. These effects of efonidipine were sustained for at least 30 min after the ET-1 administration. It is concluded that efonidipine attenuates the ET-1-induced vasoconstriction, and therefore the drug would be useful for some patients with variant angina, in which ET-1 is involved in the genesis of coronary vasoconstriction.

Laura Mabel Sanchez - One of the best experts on this subject based on the ideXlab platform.