ABSTRACT
Intracerebroventricular injection of methylenedioxymethamphetamine (MDMA, ecstasy) in rats fails to reproduce long-term toxic effects observed after peripheral administration. Therefore, systemic metabolites would play an essential role in the development of cytotoxicity. In humans, the major metabolite is the 3,4-dihydroxymethamphetamine derivative (HHMA), which is easily oxidizable to the orthoquinone species. This can either participate to redox cycling generating semiquinone radicals and reactive oxygen species (ROS), or react with endogenous thiol derivatives yielding catechol-thioether conjugates whose the toxicity is not well established. A one pot electrochemical procedure has been developed allowing the synthesis of several catechol-thioether metabolites. Two in vitro assays have been used for evaluating their specific cytotoxicity. The first one is a bacterial assay, which shows that HHMA and some catechol-thioether conjugates can induce toxic phenomena leading to the formation of ROS, through redox cycling processes involving o-quinonoid species. The second one is an assay of cellular viability, performed on rat hippocampal pyramidal neurons. It confirms that some of these metabolites exhibit a noticeable cytotoxicity by markedly eliciting both necrosis and apoptosis markers.
Subject(s)
Hallucinogens/pharmacokinetics , Hallucinogens/toxicity , N-Methyl-3,4-methylenedioxyamphetamine/pharmacokinetics , N-Methyl-3,4-methylenedioxyamphetamine/toxicity , Animals , Biological Assay , Biotransformation , Cell Survival/drug effects , Deoxyepinephrine/analogs & derivatives , Deoxyepinephrine/toxicity , Escherichia coli/drug effects , Hallucinogens/administration & dosage , Hippocampus/pathology , Injections, Intraventricular , N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage , Pyramidal Cells/drug effects , Pyramidal Cells/pathology , Rats , Reactive Oxygen SpeciesSubject(s)
Xenobiotics/metabolism , Amine Oxidase (Copper-Containing)/metabolism , Animals , Biotransformation , Cytochrome P-450 Enzyme System/metabolism , Glycation End Products, Advanced/metabolism , Humans , Oxidation-Reduction , Pharmaceutical Preparations/metabolism , Xenobiotics/pharmacokineticsABSTRACT
A series of new 8-amino-1,4-benzoxazine derivatives 5a-o was synthesized and examined for their intrinsic cytotoxicity and their capacity to inhibit oxidative stress-mediated neuronal degeneration in neuronal cell cultures. In particular, substituent effects at the 3- and 8-positions of the 1,4-benzoxazine ring were investigated by in vitro evaluation. In this aim, 3-alkyl substituents seemed to be essential for efficient neuroprotective activity. Furthermore, within the subseries of substituted 3-alkyl benzoxazines, the most active derivatives were those bearing an 8-benzylamino substituent. From the combined results of both toxicity and neuroprotection expressed in terms of the safety index, 8-benzylamino-substituted-3-alkyl-1,4-benzoxazines were identified as the most promising compounds, owing to their potent neuroprotective activity without the manifestation of intrinsic cytotoxicity.
Subject(s)
Antioxidants/chemical synthesis , Neuroprotective Agents/chemical synthesis , Oxazines/chemical synthesis , Spiro Compounds/chemical synthesis , Animals , Antioxidants/pharmacology , Benzophenones/chemistry , Benzophenones/pharmacology , Benzoxazines , Cell Death/drug effects , Cell Line , Hippocampus , Mice , Molecular Structure , Nerve Degeneration/prevention & control , Neurons/drug effects , Neuroprotective Agents/pharmacology , Oxazines/pharmacology , Oxazines/toxicity , Oxidative Stress , Psychotropic Drugs/chemistry , Psychotropic Drugs/pharmacology , Spiro Compounds/pharmacology , Spiro Compounds/toxicity , Structure-Activity RelationshipABSTRACT
In order to gain an interpretation of the schistosomicidal effect of 4-methyl 5-(2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz), chemical, electrochemical and enzymatic hypotheses are discussed from a pharmacological standpoint. The enzymatic hypothesis is in good agreement with experimental results which ascertain that oltipraz behaves as a prodrug.
Subject(s)
Glutathione Reductase/antagonists & inhibitors , Prodrugs/pharmacology , Pyrazines/pharmacology , Schistosoma/drug effects , Animals , Disulfides/blood , Disulfides/metabolism , Humans , Mice , Models, Chemical , Pyrazines/chemistry , Pyrazines/therapeutic use , Schistosoma/enzymology , Schistosomiasis/drug therapy , Sulfoxides/blood , Sulfoxides/metabolism , Thiones , ThiophenesABSTRACT
A decrease in glutathione reductase (GR) activity was observed in Schistosoma mansoni isolated from oltipraz(OPZ)-treated mice. Yeast and Schistosoma mansoni GR-activity was inhibited by OPZ derivatives only. These OPZ-derivatives showed in vitro schistosomicidal activity. Using yeast GR and dithiolium salts of OPZ, time-dependent inactivation and gel chromatography experiments revealed irreversible inhibition dependent on the redox state of the enzyme. Binding of radiolabelled ([3H]7-methyl-8-methylthio-pyrrolo[1,2-a]pyrazine disulphide 1b) obtained from OPZ was observed using exclusion chromatography and equilibrium dialysis. These results indicate that GR can be considered as the target of schistosomicidal activity of OPZ. The lack of inhibitory activity of OPZ and dithiole-thione analogues, and the potent activity of the corresponding pyrrolo-pyrazine derivatives, is consistent with the hypothesis that OPZ is a pro-drug.
Subject(s)
Glutathione Reductase/antagonists & inhibitors , Pyrazines/metabolism , Schistosoma mansoni/metabolism , Schistosomicides/metabolism , Animals , Pyrazines/pharmacology , Schistosoma mansoni/drug effects , Schistosoma mansoni/enzymology , Schistosomicides/pharmacology , Thiones , ThiophenesABSTRACT
The pKa values of acid-base equilibria involved in the protonation of zopiclone and analogues are determined by UV-visible absorption spectrometry and pH-metry. Hydrogen ion catalysis is evidenced in the carbamate hydrolysis.
Subject(s)
Piperazines/analysis , Azabicyclo Compounds , Buffers , Chemical Phenomena , Chemistry , Chromatography, Thin Layer , Half-Life , Hydrogen-Ion Concentration , Hydrolysis , Kinetics , Magnetic Resonance Spectroscopy , Piperazines/metabolism , Spectrophotometry, UltravioletABSTRACT
The pKa values of acid-base equilibria involved in the protonation of pristinamycin IA and its model compound, N-isobutyl-3-hydroxypicolinamide, were determined by UV-visible absorption spectrometry and potentiometric titration. The equilibrium between dipolar ionic and uncharged neutral forms was investigated spectrometrically in methanol-water solutions. With pristinamycin IA, the dipolar ionic form predominated in aqueous solutions buffered to the isoelectric pH. The effects of structure on the ionization constants are briefly discussed.
Subject(s)
Virginiamycin/chemistry , Chemical Phenomena , Chemistry, Physical , Chromatography, Thin Layer , Hydrogen-Ion Concentration , Isoelectric Focusing , Potentiometry , Spectrophotometry, UltravioletABSTRACT
The kinetic profile for the decomposition of ditiocarb sodium salt in aqueous solution was achieved with UV-visible absorption spectrometry. The kinetic profile indicates that the decomposition reaction is hydrogen ion-catalyzed over the entire 4-10 pH range and enables the determination of the value of the acid-base equilibrium constant (Ka = 4.0.10(-4) at 5 degrees C). Decomposition of ditiocarb produces volatile carbon disulfide, exclusive of hydrogen sulfide, as shown with electrochemical methods. This feature is of interest from a toxicological point of view.
Subject(s)
Ditiocarb/chemistry , Ditiocarb/toxicity , Hydrogen-Ion Concentration , Kinetics , Solutions , VolatilizationABSTRACT
In buffered water:methanol media, the pKa values of acid-base equilibria involved in the protonation of substituted quinolines are determined by UV-visible absorption spectrometry. The observed behavior depends on the nature of R2: the N-CH3 derivatives exist as quinoline, the N-H derivatives as 4-iminoquinoline tautomers. The iminoquinoline zwitterionic species present at physiological pH may have high receptor affinity. A linear relationship between pKa of the endocyclic nitrogen and log IC50 is discussed.
Subject(s)
Quinolines/metabolism , Receptors, Drug/metabolism , Hydrolysis , Nitrogen , Quinolines/chemistry , Spectrophotometry, Ultraviolet , Structure-Activity RelationshipABSTRACT
In order to gain an interpretation of the schistosomicidal effect of 4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (Oltipraz), chemical, electrochemical and enzymatic hypotheses are discussed from a pharmacological standpoint. The enzymatic hypothesis is in good agreement with experimental results which ascertain that Oltipraz behaves as a prodrug.
Subject(s)
Pyrazines/pharmacology , Schistosomicides/pharmacology , Electrochemistry , Glutathione Reductase/metabolism , In Vitro Techniques , Pyrazines/metabolism , Schistosomicides/metabolism , Thiones , ThiophenesABSTRACT
Injection of 3,4-methylenedioxyamphetamine (MDA) or 3,4-methylenedioxymethylamphetamine (MDMA or ecstasy) directly into the brain fails to reproduce the long-term effects observed after peripheral administration, implying an essential role for systemic metabolites in the development of toxicity. However, the precise identity of the metabolites participating in MDA and MDMA-mediated serotonergic neurotoxicity remains unclear: neither 3,4-alpha-methyldopamine, nor N-methyl-alpha-methyldopamine, major metabolites, produce neurotoxicity following peripheral administration. In vivo, these metabolites are oxidized to the corresponding orthoquinones, that readily react with protein and nonprotein sulphydryls including glutathione (GSH). The resulting quinol-thioether conjugates exhibit a variety of toxicological activities, which can be regulated by intramolecular cyclisation reactions that occur subsequent to oxidation. The ability of quinol-thioether conjugates to redox cycle and produce reactive oxygen species provides a rationale for the potential role of these metabolites in MDA and MDMA neurotoxicity. A biomimetic one-pot synthesis of 5-(GSH-S-yl)-N-Me-alpha-Me-DA involving addition of GSH to the electrogenerated orthoquinone species, is reported to evaluate its in vivo potential neurotoxicity.
Subject(s)
Amphetamines/toxicity , Hydroquinones/chemical synthesis , Neurotoxicity Syndromes/pathology , Serotonin/physiology , Sulfides/chemical synthesis , Amphetamines/pharmacokinetics , Animals , Biotransformation , Electrochemistry , Hallucinogens/pharmacokinetics , Hallucinogens/toxicity , Humans , Hydroquinones/toxicity , Molecular Mimicry , N-Methyl-3,4-methylenedioxyamphetamine/pharmacokinetics , N-Methyl-3,4-methylenedioxyamphetamine/toxicity , Sulfides/toxicityABSTRACT
The reactions of a new type of quinonoid system with benzylamine have been investigated in methanol in order to mimic the reactions occurring in the course of the enzymatic oxidation of amines by quinone cofactors. Under strictly anaerobic conditions, unstable quinonoid species 1(ox)()-4(ox)() have been selectively electrogenerated using anodic-controlled potential electrolysis. Thus, we have demonstrated that 3,4-quinone 1(ox)() is incapable of deaminating benzylamine, while 3,4-iminoquinone species 3(ox)() and 4(ox)() act as efficient catalysts for the autorecycling oxidation of benzylamine: the reaction efficiency reached 64 turnovers. Additional mechanistic investigations reveal that the oxidation of benzylamine by our quinonoid model cofactors proceeds unambiguously via a transamination mechanism, as suggested for many enzymatic systems.
Subject(s)
Benzylamines/chemistry , Oxidoreductases Acting on CH-NH Group Donors/chemistry , Quinones/chemical synthesis , Deamination , Electrochemistry , Indicators and Reagents , Mercury , Oxidation-ReductionABSTRACT
A series of orthoalkylaminophenol derivatives was synthesized and tested in vitro with respect to their neuroprotective effect. Some of these compounds exhibited a potent antioxidant activity close to that of standard alpha-tocopherol.