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2-(2'-Hydroxyphenyl)-4-aryl-1,5-benzodiazepines as CNS active agents.

1-Aryl-3(2'-hydroxyphenyl)-propane-1,3-diones (III) have been prepared by the Baker-Venkataraman transformation of the corresponding 2-substituted benzoyl-oxyacetophenones (II). The aforesaid propane-1,3-diones (III) were condensed with o-phenylene diamine to give eight benzodiazepines (IV) which have been found to be very good MAO inhibitors (in vitro), and anticonvulsant and hypnotic (in vivo) agents. Some chemical leads on pharmacological activities have been observed.

Animals↗

The antimycotic activity in vitro of five diols.

The antimycotic activity of ethane-1,2-diol, propane-1,2-diol, butane-1,3-diol, pentane-1,5-diol, and hexane-2,5-diol in vitro against Pityrosporum orbiculare, Candida albicans, Trichophyton rubrum, T. mentagrophytes var. interdigitale and Epidermophyton floccosum was studied. Ethane-1,2-diol had the lowest activity (MIC of 40-100 g 1(-1)), and hexane-2,5-diol the highest activity (MIC of 10-40 g 1(-1)). Among, the higher diols there can be both effective antifungal agents and substances with a lower risk of allergic and irritative skin reactions than propane-1,2-diol.

Antifungal Agents↗

Pharmacological characterization of LY303870: a novel, potent and selective nonpeptide substance P (neurokinin-1) receptor antagonist.

LY303870 [(R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- (piperidin-1-yl)piperidin-1-yl)acetyl)amino]propane] is a new, potent and selective nonpeptide neurokinin-1 (NK-1) receptor antagonist. LY303870 bound selectively and with high affinity to human peripheral (Ki = 0.15 nM) and central (Ki = 0.10 nM) NK-1 receptors. LY303870 inhibited [125I]substance P (SP) binding to guinea pig brain homogenates with similar affinity; however, it had approximately 50-fold lesser affinity for rat NK-1 sites. The less active enantiomer, LY306155 [(S)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- (piperidin-1-yl)piperidin-1-yl)acetyl)amino]-propane], was 1,000- to 15,000-fold less potent in all the species examined. LY303870 antagonized in vitro NK-1 receptor effects as demonstrated by blockade of SP-stimulated phosphoinositide turnover in UC-11 MG human astrocytoma cells (Ki = 1.5 nM) and interleukin-6 secretion from U-373 MG human astrocytoma cells (Ki = 5 nM). In addition, LY303870 inhibited SP-induced rabbit vena cava contractions (pA2 = 9.4) with high (50,000-fold) selectivity vs. NK-2 or NK-3 receptor-mediated responses. In vivo, LY303870 inhibited [Sar9,Met(O2)11]-SP induced guinea pig bronchoconstriction (ED50 = 75 micrograms/kg i.v.) and pulmonary microvascular leakage in the bronchi (ED50 = 12.8 micrograms/kg i.v.) and trachea (ED50 = 18.5 micrograms/kg i.v.). Therefore, LY303870 is a potent and selective NK-1 receptor antagonist in vitro and in vivo. The use of LY303870 will facilitate a better understanding of NK-1 receptors in physiological processes.

Airway Resistance↗

9-Aminoacridines act at a site different from that for Mg2+ in blockade of the N-methyl-D-aspartate receptor channel.

The effects of alkylene bis-9,9'-aminoacridines and 1,2,3,4-tetrahydro-9-aminoacridine (THA) were studied on single-channel currents activated by N-methyl-D-aspartate (NMDA) in outside-out patches from cultured rat hippocampal neurons. These compounds reduced the channel open times with concentration and voltage dependence, which was consistent with an open-channel blockade mechanism of action. In nominally Mg(2+)-free solutions, the forward blocking rate constants for 1,2-propane-bis-9,9'-aminoacridine, 1,4-butane-9,9'-aminoacridine, and THA were 1.1 x 10(8), 1.4 x 10(8), and 3.5 x 10(7) M-1 sec-1, respectively, at a holding potential of -80 mV. The unblocking rate constants for the bis-9-aminoacridines were similar and in the range of 7 sec-1, whereas THA had an unblocking rate constant of approximately 6.2 x 10(3) sec-1. In the presence of Mg2+ (approximately 5 microM), the predictions of the model for open-channel blockade by the 9-aminoacridines were invalid, because the relationships between the channel lifetimes and 9-aminoacridine concentrations were not linear. The effects of Mg2+ (approximately 0-50 microM) on the open-channel blockade of the NMDA receptor by the 9-aminoacridines were evaluated further by measuring the burst times in the presence of 1,2-propane-bis-9,9'-aminoacridine (5 microM). The results suggested that the interactions of 9-aminoacridines and Mg2+ with the ion channel of the NMDA receptor were not mutually exclusive. Simultaneous occupancy of the NMDA receptor ion channel by Mg2+ and a channel-blocking organic cation could be a common mechanism of channel blockade for this receptor under physiological conditions.

Aminacrine↗

Electron probe X-ray microanalysis of epithelial cells: aspects of cryofixation.

Content and distribution of diffusible ions in epithelial cells were studied by scanning transmission electron microscopy and energy dispersive electron probe X-ray microanalysis of freeze-dried cryosections from trout kidney, rat liver and Malpighian tubules of Drosophila larvae. Cryofixation of small excised kidney and liver samples by rapid immersion into liquid propane resulted in intracellular K/Na-ratios < 1. In contrast, K/Na-ratios > 7 were obtained after in situ cryofixation by means of a cryopunching device which allows tissue pieces to be frozen during excision from the intact organ. Isolated hepatocytes cryofixed in a small droplet of culture medium had a K/Na-ratio of 3.7. After culturing the hepatocytes, the K/Na-ratio increased to 24. Effects of extracellular media of different composition on the intracellular element content were studied. Malpighian tubules of Drosophila larvae were cryofixed by rapid immersion into liquid propane, and the distribution of K across the cells forming the tubules from the basal to the apical cell membrane was measured. An increasing K gradient was found from the intermediate to the apical cytoplasm. The intracellular K distribution was dependent on ions and transport inhibitors present in the fluid surrounding the Malpighian tubules within the larvae. Content and distribution of ions in epithelial cells sensitively depend on the physiological state immediately before cryofixation. Thus, electron probe X-ray microanalysis of cells and cell functions requires careful selection and control of the cell system to be studied.

Animals↗

An in vitro evaluation of a copolymerizable type of microfilled composite resin.

Prepolymerizing microfilled composite resins have gained acceptance as restorative materials. However, when used as a posterior material, many of them undergo debonding of the organic filler. Such a condition has been attributed to the fact that the filler particles are held to the surface of the resin matrix primarily by mechanical means. Recently, a composite resin has been developed in which the prepolymerized organic particle is bonded chemically to the resin matrix through copolymerization. The material consists of trimethyol propane trimethacrylate, and the numerous double bonds on the surface provide a means for chemical bonding. A three-bodied wear-testing device was used in conjunction with a series of experimental trimethyol propane trimethacrylate-containing polymers, and it was shown that most of these systems offered greater resistance to wear and marginal deterioration than did conventional systems.

Analysis of Variance↗

[Compounds, similar to acyclovir. VIII. Synthesis and antiviral activity of (R/S)-5-hydroxy-4-hydroxymethyl-3-oxapent-2-yl derivatives of nucleic bases].

The (R/S)-5-hydroxy-4-hydroxymethyl-3-oxapent-2-yl derivatives of the uracil, thymidine, cytosine, adenine, guanine and 1,2,4-triazol-3-carboxamide were synthesized using 1,3-diacetoxy-2-(1-acetoxy)propane and 1,3-dichloro-2-(1-chlorethoxy)propane as alkylating agents. The guanine derivatives exhibited activity against HSV-1 (chemotherapeutic index 32).

Acyclovir↗

Urinary excretion of phenolic metabolites of N-(n-propyl)amphetamine in man.

In vivo metabolism of (+)-N-(n-propyl)amphetamine (NPA) in man (2 subjects) produced, among other products, two conjugated phenolic metabolites which are identified as 1-(4-hydroxyphenyl)-2-(n-propylamino)propane and 1-(4-hydroxy-3-methoxyphenyl)-2-n-propylamino)propane. In a 24 hr urine sample (pH uncontrolled), 13.4% of the NPA administered was excreted as the former, and 3.5% as the latter metabolite.

Adult↗

Characterization of air quality problems in five Finnish indoor ice arenas.

The air quality in five Finnish ice arenas with different volumes, ventilation systems, and resurfacer power sources (propane, gasoline, electric) was monitored during a usual training evening and a standardized, simulated ice hockey game. The measurements included continuous recording of carbon monoxide (CO), nitric oxide (NO), and nitrogen dioxide (NO2) concentrations, and sampling and analysis of volatile organic compounds (VOCs). Emissions from the ice resurfacers with combustion engines caused indoor air quality problems in all ice arenas. The highest 1-hour average CO and NO2 concentrations ranged from 20 to 33 mg/m3 (17 to 29 ppm) and 270 to 7440 micrograms/m3 (0.14 to 3.96 ppm), respectively. The 3-hour total VOC concentrations ranged from 150 to 1200 micrograms/m3. The highest CO and VOC levels were measured in the arena in which a gasoline-fueled resurfacer was used. The highest NO2 levels were measured in small ice arenas with propane-fueled ice resurfacers and insufficient ventilation. In these arenas, the indoor NO2 levels were about 100 times the levels measured in ambient outdoor air, and the highest 1-hour concentrations were about 20 times the national and World Health Organization (WHO) health-based air quality guidelines. The air quality was fully acceptable only in the arena with an electric resurfacer. The present study showed that the air quality problems of indoor ice arenas may vary with the fuel type of resurfacer and the volume and ventilation of arena building. It also confirmed that there are severe air quality problems in Finnish ice arenas similar to those previously described in North America.

Air Pollution, Indoor↗

Toxicity effects of compressed and supercritical solvents on thermophilic microbial metabolism.

Selection of biocompatible solvents is critical when designing bioprocessing applications for the in situ biphasic extraction of metabolic end-products. The prediction of the biocompatibility of supercritical and compressed solvents is more complicated than for liquid solvents, because their properties can change significantly with pressure and temperature. The activity of the anaerobic thermophilic bacterium, Clostridium thermocellum, was studied when the organism was incubated in the presence of compressed nitrogen, ethane, and propane at 333 K and multiple pressures. The metabolic activity of the organisms in contact with compressed solvents was analyzed using traditional indicators of solvent biocompatibility, such as log P, interfacial tension, and solvent density. The toxicity of the compressed solvents was compared with the phase and molecular toxicity effects measured in liquid alkanes at atmospheric pressure. Inactivation increased with time in the presence of the compressed solvents, but was constant in the presence of atmospheric liquid solvents. Knowledge of molecular and phase toxicity provides a framework for the interpretation of C. thermocellum metabolism in contact with atmospheric and compressed solvents.

Clostridium↗

Cobalt-catalyzed cross-coupling reactions of alkyl halides with allylic and benzylic Grignard reagents and their application to tandem radical cyclization/cross-coupling reactions.

Details of cobalt-catalyzed cross-coupling reactions of alkyl halides with allylic Grignard reagents are disclosed. A combination of cobalt(II) chloride and 1,2-bis(diphenylphosphino)ethane (DPPE) or 1,3-bis(diphenylphosphino)propane (DPPP) is suitable as a precatalyst and allows secondary and tertiary alkyl halides--as well as primary ones--to be employed as coupling partners for allyl Grignard reagents. The reaction offers a facile synthesis of quaternary carbon centers, which has practically never been possible with palladium, nickel, and copper catalysts. Benzyl, methallyl, and crotyl Grignard reagents can all couple with alkyl halides. The benzylation definitely requires DPPE or DPPP as a ligand. The reaction mechanism should include the generation of an alkyl radical from the parent alkyl halide. The mechanism can be interpreted in terms of a tandem radical cyclization/cross-coupling reaction. In addition, serendipitous tandem radical cyclization/cyclopropanation/carbonyl allylation of 5-alkoxy-6-halo-4-oxa-1-hexene derivatives is also described. The intermediacy of a carbon-centered radical results in the loss of the original stereochemistry of the parent alkyl halides, creating the potential for asymmetric cross-coupling of racemic alkyl halides.

Alkylation↗

The role of Mg2+ and specific amino acid residues in the catalytic reaction of the major human abasic endonuclease: new insights from EDTA-resistant incision of acyclic abasic site analogs and site-directed mutagenesis.

Ape1, the major protein responsible for excising apurinic/apyrimidinic (AP) sites from DNA, cleaves 5' to natural AP sites via a hydrolytic reaction involving Mg2+. We report here that while Ape1 incision of the AP site analog tetrahydrofuran (F-DNA) was approximately 7300-fold reduced in 4 mM EDTA relative to Mg2+, cleavage of ethane (E-DNA) and propane (P-DNA) acyclic abasic site analogs was only 20 and 30-fold lower, respectively, in EDTA compared to Mg2+. This finding suggests that the primary role of the metal ion is to promote a conformational change in the ring-containing abasic DNA, priming it for enzyme-mediated hydrolysis. Mutating the proposed metal-coordinating residue E96 to A or Q resulted in a approximately 600-fold reduced incision activity for both P and F-DNA in Mg2+compared to wild-type. These mutants, while retaining full binding activity for acyclic P-DNA, were unable to incise this substrate in EDTA, pointing to an alternative or an additional function for E96 besides Mg2+-coordination. Other residues proposed to be involved in metal coordination were mutated (D70A, D70R, D308A and D308S), but displayed a relatively minor loss of incision activity for F and P-DNA in Mg2+, indicating a non-essential function for these amino acid residues. Mutations at Y171 resulted in a 5000-fold reduced incision activity. A Y171H mutant was fourfold less active than a Y171F mutant, providing evidence that Y171 does not operate as the proton donor in catalysis and that the additional role of E96 may be in establishing the appropriate active site environment via a hydrogen-bonding network involving Y171. D210A and D210N mutant proteins exhibited a approximately 25,000-fold reduced incision activity, indicating a critical role for this residue in the catalytic reaction. A D210H mutant was 15 to 20-fold more active than the mutants D210A or D210N, establishing that D210 likely operates as the leaving group proton donor.

Alkanes↗

Volatile alkanes produced by erythrocytes: an assay for in vitro studies on lipid peroxidation.

Lipid peroxidation in erythrocytes is currently studied by measuring the formation of malonyldialdehyde (MDA). A new and simple methodological approach to the measurement of the extend of lipid peroxidation is described here. Erythrocytes from freshly drawn human blood were washed and suspended in isoosmotic phosphate-buffered saline and incubated with sodium azide to inhibit the catalase. Oxidation of red cell lipids was induced by the addition of hydrogen peroxide. MDA formation was measured by the 2-thiobarbituric acid (TBA) reaction. After the same procedure of incubation the production of volatile alkanes (pentane, ethane, ethylene, n-butane, and propane) was estimated by gas chromatography. The total amount of pentane formation from red cells after 120 min of incubation with hydrogen peroxide was much higher than of the other alkanes. This assay provides a useful model to elucidate the role of lipid peroxidation of erythrocytes and is a simple method to study changes in their membrane lipid in diseases and red cell aging.

Alkanes↗

Microbial assimilation of alkyl nitro compounds and formation of nitrite.

66 representative strains of bacteria, yeasts and fungi were tested for their ability to grow in a semidefined medium containing 0.5% nitroethane as a nitrogen source. About half of them were found capable of growing in the medium. Hansenula beijerinckii, Candida utilis, and Penicillium chrysogenum were most active in assimilating nitroethane. 2-Nitropropane inhibited growth of most of the microorganisms tested in a medium containing 0.2% peptone and 0.2% glycerol. Hansenula mrakii was found to grow rapidly in the nitroethane-peptone medium after a lag phase. Nitrite was accumulated in the culture fluid after the phase of logarithmic multiplication, and increased with increase of the growth, followed by a decline after the maximum growth. The alkyl nitro compounds were oxidatively denitrified to form nitrite by the crude enzyme from Hansenula mrakii. Nitroethane was generally a poor substrate, but was the best inducer to produce the nitro compounds oxidizing enzyme. 2-Nitro-propane and nitroethane were enzymatically oxidized to nitrite, and acetone and acetaldehyde, respectively, which were isolated as 2,4-dinitrophenylhydrazones and identified. Nitrite formed was found to be reduced into ammonia by the intact cells and also the crude enzyme.

Acetaldehyde↗

Breath alkanes determination in ulcerative colitis and Crohn's disease.

PURPOSE: By considering the pathophysiologic basis of inflammatory bowel diseases, a role for excessive lipid peroxidation caused by oxygen free radical compounds has been proposed repeatedly. However, to date only a few studies are available on this topic in human beings. This study was designed to assess breath alkanes in a group of patients with active inflammatory bowel disease by a technique that clearly distinguishes pentane from isoprene, to prevent overestimation of values as in previous studies. PATIENTS: Twenty patients with a diagnosis of active inflammatory bowel disease (10 with Crohn's disease and 10 with ulcerative colitis) were studied. Extension of the disease was similar between patient groups, and all were treated with equivalent doses of steroids and salicylates. METHODS: Breath alkanes determination was performed by a standard procedure involving a gas chromatography column able to separate pentane from isoprene. RESULTS: Overall, significant differences between patients with inflammatory bowel diseases and controls were found for ethane, propane, and pentane, but not for butane and isoprene. Isoprene was clearly distinguished from pentane, demonstrating that the significant elevation of pentane levels in patients with inflammatory bowel diseases is a real phenomenon and not an artifact caused by coelution with isoprene. CONCLUSIONS: An excess of lipid peroxidation is probably an important pathogenetic factor in inflammatory bowel diseases, and this may be assessed through a noninvasive method. Because this method previously also has been shown to be able to evaluate disease activity, it could be a useful tool for studying patients with inflammatory bowel diseases.

Adolescent↗

Co-metabolic degradation of chlorinated hydrocarbons by Pseudomonas sp. strain DCA1.

Pseudomonas sp. strain DCA1, which is capable of utilizing 1,2-dichloroethane (DCA) as sole carbon and energy source, was used to oxidize chlorinated methanes, ethanes, propanes, and ethenes. Chloroacetic acid, an intermediate in the DCA degradation pathway of strain DCA1, was used as a co-substrate since it was readily oxidized by DCA-grown cells of strain DCAI and did not compete for the monooxygenase. All of the tested compounds except tetrachloroethylene (PER) were oxidized by cells expressing DCA monooxygenase. Strain DCAI could not utilize any of these compounds as a growth substrate. Co-metabolic oxidation during growth on DCA was studied with 1,2-dichloropropane. Although growth on this mixture occurred, 1,2-dichloropropane strongly inhibited growth of strain DCAI. This inhibition was not caused by competition for the monooxygenase. It was shown that the oxidation of 1,2dichloropropane resulted in the accumulation of 2,3-dichloro-1-propanol and 2-chloroethanol.

Acetates↗

Effects of gaseous anaesthetics and inert gases on the phase transition in smectic mesophases of dipalmitoyl phosphatidylcholine.

The phase transition in smectic mesophase of dipalmitoyl phosphatidyl-choline was studied under high pressures of helium (340 atm), nitrogen (340 atm), nitrous oxide (43 atm), cyclopropane (4.4 atm) and n-propane (8.2 atm), using a turbidimetric technique. Helium and nitrogen increased the transition temperature by 0.021 and 0.006 degree C/atm, respectively, compared with 0.024 degrees C/atm for hydrostatic pressure. Nitrous oxide reduced the transition by 0.58 degree C/atm. The hydrocarbon gases spread the transition width and lowered the transition temperature with increasing effect at higher doses. Comparisons with other membrane probes are made and the concentration of gases in the bilayer which lower the transition temperature by 1 degree C are estimated, in mol%: He, 10.2; N2, 13.2: N2O, 9.04; n-C3H8, 6.3 and cyclopropane, 12.8.

Anesthetics↗

Metabolism of the genotoxicant 2-nitropropane to a nitric oxide species.

The mechanisms by which the paint constituent 2-nitropropane (2-NP) exerts genotoxicity and hepatocarcinogenicity are poorly understood. The hypothesis was tested that nitric oxide (NO) is a hepatic metabolic intermediate generated from 2-NP and/or its anionic tautomer propane 2-nitronate (P2N). Incubations of liver microsomes from phenobarbital-pretreated rats or mice with 2-NP or P2N gave spectra with Soret maxima at 448 nm which indicated the presence of a ferrous-NO complex. Levels of 3':5'-cyclic guanosine monophosphate (cGMP) and nitrite were measured by ELISA assay and HPLC, respectively, in freshly isolated mouse hepatocytes. Levels of cGMP generated within 3 h in cells by 2-NP, P2N (5 mM each) or the diethylamine/NO complex [Et2NNO(N==O)]Na (0.6 mM), an NO precursor, were 6, 15 and 34 times, respectively, those seen in control hepatocytes. Production of cGMP following treatment with 2-NP was linear with time of incubation; cGMP generation from P2N reached its peak already after 1 h. cGMP levels observed in incubates with 1-nitropropane and 2-deutero 2-nitropropane (5 mM), 2-NP isomers devoid of genotoxic properties, were significantly lower than those seen in the presence of 2-NP. Inclusion in the incubate of methylene blue, which inhibits NO-mediated reactions, decreased cGMP formation in hepatocytes with [Et2NNO(N==O)]Na, but increased it in cells with 2-NP or P2N. The production of nitrite from 2-NP, P2N or [Et2NNO(N==O)]Na mirrored cGMP formation. The results suggest that 2-NP and its nitronate generate an NO species in cells which may mediate, or contribute to, 2-NP genotoxicity.

Animals↗