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Detections of opioid receptors in plasma membranes. Binding assays with specific radioligands
Višněvská, Kateřina ; Hudeček, Jiří (advisor) ; Wilhelm, Jiří (referee)
Morphin is an important opioid drug which is used in medicine as a highly potent analgesic in treatment of both acute and chronic pain, post-traumatic shock and diarrhea. However, in treatment of chronic pain, the serious problem is represented by step-by-step development of decreased sensitivity of physiological response to morphine exposure (tolerance) and, subsequently, the psychological as well as physical dependence on this drug. Opioids interact with three types of opioid receptors: μ-OR, δ-OR and κ-OR. One of primary goals of many pharmaceutical companies is an effort to design more specific and simultaneously potent OR agonists, which would exhibit highly efficacious analgesic effects, but would not develop fast physical dependence in conditions of the long-term usage. In our work, the primary attention was devoted to μ-OR because these receptors are primarily responsible for physiological effect of morphine and genesis of tolerance and drug dependence. We studied the binding of specific agonist [3 H]DAMGO to plasma membranes (PM) isolated from rat brain cortex of rats adapted to increasing doses of morphine (10-50 mg/kg) for 10 days. PM isolated by centrifugation in Percoll density gradient from morphine-adapted rats exhibited the decrease of maximum binding capacity Bmax of this...
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Detections of opioid receptors in plasma membranes. Binding assays with specific radioligands
Višněvská, Kateřina ; Hudeček, Jiří (advisor) ; Wilhelm, Jiří (referee)
Morphin is an important opioid drug which is used in medicine as a highly potent analgesic in treatment of both acute and chronic pain, post-traumatic shock and diarrhea. However, in treatment of chronic pain, the serious problem is represented by step-by-step development of decreased sensitivity of physiological response to morphine exposure (tolerance) and, subsequently, the psychological as well as physical dependence on this drug. Opioids interact with three types of opioid receptors: μ-OR, δ-OR and κ-OR. One of primary goals of many pharmaceutical companies is an effort to design more specific and simultaneously potent OR agonists, which would exhibit highly efficacious analgesic effects, but would not develop fast physical dependence in conditions of the long-term usage. In our work, the primary attention was devoted to μ-OR because these receptors are primarily responsible for physiological effect of morphine and genesis of tolerance and drug dependence. We studied the binding of specific agonist [3 H]DAMGO to plasma membranes (PM) isolated from rat brain cortex of rats adapted to increasing doses of morphine (10-50 mg/kg) for 10 days. PM isolated by centrifugation in Percoll density gradient from morphine-adapted rats exhibited the decrease of maximum binding capacity Bmax of this...
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Plant alkaloids and their effects on enzymes metabolizing xenobiotics
Višněvská, Kateřina ; Stiborová, Marie (advisor) ; Černá, Věra (referee)
Sanguinarine and chelerythrine are quaternary benzo[c]phenanthridine alkaloids. The first step in sanguinarine metabolism is its reduction to dihydrosanguinarin. Antimicrobial and anti-inflammatory activities of these alkaloids are used in dentistry and as feed additives. Sanguinarine and chelerythrine induce apoptosis of cells. Fluorescence of these alkaloids and intercalation into DNA could be utilized to use the alkaloids as supravital DNA probe. Negative effect of sanguinarine and chelerythrine is their genotoxicity. Cytochrome P450 and peroxidase oxidize ellipticine to detoxication and activation metabolites. Ellipticine is a potent antineoplastic agent exhibiting the multimodal mechanism of its action. Ellipticine intercalates into DNA and inhibits topoisomerase II. Covalent DNA aducts are mediated by CYP or peroxidase oxidation of ellipticine. The anti-tumor activity of ellipticine and its derivatives is caused by a combination mechanism of cell cycle arrest and induction of the apoptotic pathway. Pharmacological efficiencies and geneotoxic side effects of ellipticine is dependent on levels and activities of cytochrome P450 or peroxidase in target tissues. Aristolactams are the major metabolites of biotransformation of aristolochic acid. Nitroreduction is the crucial step in formation of an...
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