Synthesis and activity of a new class of heterocyclic compounds against Entamoeba histolytica. 1,2,3,3a-tetrahydro-1-alkylcyclopenta[de]quinolines.
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Animals↗
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Results for “Quinolinium Compounds”
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Involvement of platelet activating factor and thromboxane A2 in the renal response to unilateral ureteral obstruction.
Platelet activating factor (PAF) and thromboxane A2 (TxA2) are two vasoactive mediators which can decrease renal blood flow. Both are synthesized by various intrarenal cell types or by macrophages which may infiltrate the kidney during unilateral ureteral obstruction (UUO). In several experimental systems, PAF receptor activation is accompanied by TxA2 release; pharmacological modification of TxA2 synthesis or receptor activation modulates the response to PAF. The involvement of PAF in UUO has not been studied previously, and the role of TxA2 has not been clearly defined by previous investigations. The hemodynamic response to acute UUO is characterized by decreases in renal blood flow (RBF) and glomerular filtration rate and an acute increase in ureteral pressure. In the present experiments, the involvement of either PAF or TxA2 in the acute response to UUO was studied by determining if blockade of either the TxA2 or PAF receptor would affect the renal hemodynamic response to UUO. In addition, the effect of blockade of the TxA2 receptor on the renal response to PAF was determined. Our results indicate that only a small portion of the renal response to PAF is mediated by TxA2, and that neither PAF nor TxA2 can be implicated in the acute hemodynamic response to UUO. TxA2 or PAF involvement in the chronic response to UUO still remains to be determined.
Animals↗
On the use of nonfluorescent dye labeled ligands in FRET-based receptor binding studies.
The efficiency of fluorescence resonance energy transfer (FRET) is dependent upon donor-acceptor proximity and spectral overlap, whether the acceptor partner is fluorescent or not. We report here on the design, synthesis, and characterization of two novel pirenzepine derivatives that were coupled to patent blue VF and pinacyanol dyes. These nonfluorescent compounds, when added to cells stably expressing enhanced green fluorescent protein (EGFP)-fused muscarinic M1 receptors, promote EGFP fluorescence extinction in a time-, concentration-, and atropine-dependent manner. They display nanomolar affinity for the muscarinic receptor, determined using either FRET or classical radioligand binding conditions. We provide evidence that these compounds behave as potent acceptors of energy from excited EGFP with quenching efficiencies comparable to those of analogous fluorescent bodipy or rhodamine red pirenzepine derivatives. The advantages they offer over fluorescent ligands are illustrated and discussed in terms of reliability, sensitivity, and wider applicability of FRET-based receptor binding assays.
Benzenesulfonates↗
A rapid detection of PCR amplification product using a new fluorescent intercalator; the pyrylium dye, P2.
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Actins↗
Antitumor activity of some quaternary ammonium compounds. Structure-activity relationship.
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Animals↗
Clinical application of a novel DNA fluorescence intercalator, pyrylium dye, for the quantification of PCR products.
Polymerase chain reaction (PCR) is a powerful tool for clinical diagnosis in the field of oncology, infection, and allergy. However, a simple and sensitive method for quantifying PCR products has not been established. We therefore used a novel fluorescence DNA intercalator, pyrylium iodide (P2) to quantify PCR products. A 838-bp fragment of the human beta-actin gene and a 374-bp fragment of the gene for ornithine decarboxylase (ODC) and ODC primer dimers were generated by PCR and quantified using either P2 or another fluorescence DNA intercalator, YOYO-1. In addition, utilizing RT-PCR and the P2 method, the ODC mRNA expression from 10 colonic cancers was quantified. Serially diluted beta-actin and ODC PCR products could be quantified using P2 without having to separate them from primer dimers and other components of the reaction mixture. However, YOYO-1 could not be used to quantify the PCR products because of high background fluorescence from the primer dimers. In the clinical study, ODC mRNA expression as quantified by P2 was significantly higher in cancerous tissue (113.8 +/- 4.1; mean +/- SEM; plate reader units) than in mucosa of normal appearance (68.4 +/- 4.8). P2 is a promising tool for quantifying PCR products.
Actins↗
Studies of catalysis by acetylcholinesterase. Synergistic effects of inhibitors during the hydrolysis of acetic acid esters.
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Acetates↗
Identification of a pharmacophore of SKCa channel blockers.
Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system (CNS) and the periphery. Three subtypes of SK channels have so far been identified in different parts of the brain. Activation of the SK channels by a rise in intracellular calcium leads to the hyperpolarisation of the membrane, reducing cell excitability. Blocking the SK channels might be beneficial in the treatment of depression, Parkinson's disease and cognitive disorders. However, few blockers of SK channels have been characterized. In this study, a pharmacophoric model of SK channels blockers is presented. It is based on a series of nonpeptidic compounds and apamin, a peptidic blocker. To create the pharmacophore model, the conformational space of nonpeptidic blockers was investigated to generate a series of distance constraints applied to a simulated annealing study of apamin. The resulting conformation was superimposed with the nonpeptidic blockers to give a pharmacophore.
Amino Acid Sequence↗
Synthesis and antimalarial activity of E-2-quinolinylbenzocycloalcanones.
A series of E-2-quinolinylbenzocycloalcanones 5-21 were prepared and evaluated for their activity to inhibit beta-hematin formation and the hydrolysis of hemoglobin in vitro. Positive compounds for both assays were also tested for their efficacy in rodent Plasmodium berghei. Compounds 6, 16, 19, and 20, were the most promising. Inhibition of beta-hematin formation was minimal when a hydrogen or methoxy groups were present on the position 8 of the quinoline and position 4' of the indanone ring as it appeared for compounds 5, 7-15, 17, 18, and 21, and greatest with compounds (52%) and (90%) with a substitution of methoxy on position 6 and 7 or methyl on position 8 of the quinoline nucleus and methoxy or methyl groups on position 4' of the indanone. The most active compound to emerge from this study is 2-chloro-8-methyl-3-[(4'-methoxy-1'-indanoyl)-2'-methyliden]-quinoline 20 effective as antimalarial that target beta-hematin formation and the inhibition of the hydrolysis of hemoglobin in vitro together with a good survival in a murine malaria model, which should help delay the rapid onset of resistance to drugs acting at only a single site. Results with these assays suggest that quinolinylbenzocycloalcanones exert their antimalarial activity via multiple mechanisms.
Animals↗
6-substituted 1-methylquinolinium-2-dithioacetic acid zwitterions: antileukemia activity.
Condensation of the anhydro bases derived from 6-substituted 1-methylquinaldinium iodides with carbon disulfide provided the 2-dithioacetic acid zwitterions. Since 1.6-dimethylquinolinium-2-dithioacetic acid zwitterion previously showed appreciable activity against P-388 lymphocytic leukemia in mice, a series of analogs with other 6-substituents was synthesized to assess the importance of substitution in this position. Both electron-donating and electron-attracting 6-substituents gave compounds with antileukemia activity. The 6-unsubstituted analog had only marginal activity.
Animals↗
Structure and dynamics of condensed DNA probed by 1,1'-(4,4,8,8-tetramethyl-4,8-diazaundecamethylene)bis[4-[[3- methylbenz-1,3-oxazol-2-yl]methylidine]-1,4-dihydroquinolinium] tetraiodide fluorescence.
Information on the structure and dynamics of condensed forms of DNA is important in understanding both natural situations such as DNA packaging and artificial systems such as gene delivery complexes. We have established the fluorescence of bisintercalator 1,1'-(4,4,8,8-tetramethyl-4,8-diazaundecamethylene)bis[4-[[3-methylbenz-1,3-oxazol-2-yl]methylidine]-1,4-dihydroquinolinium] tetraiodide (YOYO-1) as a novel probe for DNA condensation. When the level of DNA-bound YOYO-1 is sufficiently large, condensation by either polyethylenimine (PEI) or the cationic detergent cetyltrimethylammonium bromide (CTAB) leads to electronic interaction among YOYO-1 molecules bound on the same DNA molecule. This interaction results in an excitonic blue shift of the absorption spectra of YOYO-1 and dramatic decrease in the fluorescence quantum yield. These observations constitute a signature of the condensation of DNA. We further examined the comparative properties of DNA condensed by PEI, CTAB, or Co(NH(3))(6)(3+) through the steady-state and dynamic fluorescence of YOYO-1. Condensation by either PEI or CTAB was associated with a blue shift in the absorption spectra of YOYO-1, although the magnitude of the shift was larger in the case of PEI when compared to that of CTAB. In contrast, condensation by Co(NH(3))(6)(3+) was not associated with a measurable shift in the absorption spectra. These results were interpreted as signifying the varying level of compactness of the DNA condensates. Quenching of fluorescence by acrylamide showed that condensation by all three agents led to an increase in the level of solvent exposure of the base pairs. Observation of the decay of fluorescence intensity and anisotropy of DNA-bound YOYO-1 showed that while condensation by either PEI or CTAB froze the segmental mobility of the helix, condensation by Co(NH(3))(6)(3+) enhanced the flexibility of DNA. The relevance of our findings to functions such as efficiency of gene delivery is discussed.
Benzoxazoles↗
Synthesis and antileukemic activity of 2-(2-methylthio-2-aminovinyl)-1-methylquinolinium iodides.
Reaction of 2-bis(2-methylthio)vinyl-1-methylquinolinium iodide with several heterocyclic aliphatic amines at 30-70 degrees resulted in replacement of one methylthio group to give the title compounds. Reaction with pyrrolidine gave an unidentified product lacking sulfur. Antileukemic screening against P-388 lymphocytic leukemia showed positive activity only with the 6-methyl-morpholino derivative, whereas the 6-unsubstituted morpholino derivative was inactive. This result is in contrast to previous testing results with the 2-bis(2-methylthio)vinyl compounds where both 6-substituted and 6-unsubstituted derivatives showed activity.
Animals↗
Gene transfer by cationic surfactants is essentially limited by the trapping of the surfactant/DNA complexes onto the cell membrane: a fluorescence investigation.
The interaction between complexes of plasmid DNA with cetyltrimethylammonium bromide (CTAB) and L929 fibroblasts was first examined using confocal microscopy. The complexes labeled with the DNA intercalator, YOYO-1, were found to be trapped onto the external face of the plasma membrane; a feature that may constitute a major limiting step in transfection. Moreover, since no cytotoxic effect appeared in these conditions, we further inferred that the CTAB molecules remained bound to the DNA. The interaction of the complexes with the membranes was best modeled with neutral vesicles. From anisotropy thermotropic curves of DPHpPC-labeled vesicles and fluorescence resonance energy transfer measurements between these vesicles and YOYO-labeled complexes, we evidenced that the binding of the complexes to the vesicle surface opened the micelle-like domains and unwound DNA. However, DNA was not released but remained stably bound via electrostatic interactions to the CTAB molecules incorporated in the external liposome leaflet. Consequently, the large diameter of the unwound plasmid DNA is likely the major factor that precludes its internalization into the cells by endocytosis. In contrast, anionic vesicles that mimic the cytoplasmic facing monolayer of the plasma membrane rapidly released DNA from the complex. This may explain the previously reported high transfection efficiency of DNA complexed with liposomes composed of neutral lipids and cationic surfactants, since the latter may destabilize the endosomal membrane and induce the release of DNA in the cytoplasm.
Animals↗
[The efficacy of dequalinium chloride/benzalkonium chloride as well as medicinal plants on the gingiva].
A comparative study involving 50 patients of both genders was conducted in order to determine the effect of dequalinium chloride/benzalconium chloride mouthrinse (Dequonal), and of a preparation of herbal essences (Parodontax) on gingival health. Each of the mouthrinses was used during four weeks by a group of 25 patients who were instructed to abstain from any other oral hygiene measure during this period. Approximal plaque index, sulcus bleeding index and saliva pH were significantly enhanced by both preparations. A slightly better effect shown by dequalinium chloride/benzalconium chloride was not significant.
Adult↗
Potent reversible anticholinesterase agents. Bis- and mono-N-substituted benzoquinolinium halides.
A number of bis- and mono-N-substituted benzoquinolinium salts and their analogues were prepared and evaluated as inhibitors of acetylcholinesterase (AcChE) and butyrylcholinesterase (BuChE). These compounds were also used to help identify some of the morphologic characteristics of the surface at or near the active sites of the cholinesterases. The shape, size, configuration, and conformation of the onium moieties of the quaternary ammonium compounds were found to be the important factors in their anticholinesterase activity. A high concentration of the positive charge of the quaternary ammonium compound is not a critical factor for the cholinesterase inhibitory activity. The order of decreasing potency of cholinesterase inhibition of the benzoquinolinium compounds was found to be acridinium greater than phenanthridinium greater than 5,6-benzoquinolinium greater than 7,8-benzoquinolinium. The inhibitory activity of the monobenzoquinolinium halides against cholinesterases is influenced by the N-substituent. A bis-quaternary ammonium compound with a flexible bridge that links the two nitrogen atoms was found to be more potent in inhibiting AcChE and less potent in inhibiting BuChE than a bis-quaternary ammonium compound with a rigid bridge. The acridinium and phenanthridinium derivatives of the benzoquinolinium compounds are very potent reversible inhibitors against both AcChE and BuChE.
Cholinesterase Inhibitors↗
[Actions of new iminium compounds on selected bacterial and fungal strains. 10. Synthesis of N-alkoxymethylquinolinium chlorides and their derivatives].
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Anti-Bacterial Agents↗
4-Acetoxy-1,2,3,4-tetrahydro-2,2-dimethyl-6,7-methylenedioxyisoquinolinium iodide, an acetylcholine analog.
4-Acetoxy-1,2,3,4-tetrahydro-2,2-dimethyl-6,7-methylenedioxyisoquinolinium iodide, an analog of acetylcholine, was synthesized and a pharmacological profile of its GI effects was compiled. The agent inhibited dog colonic contraction in response to pelvic nerve stimulation and to acetylcholine. In rats, the compound markedly reduced gastric acid output and the volume of gastric secretions. The lack of inhibition of chromodacryorrhea production in response to carbachol indicates a lack of anticholinergic action. The agent failed to affect the acute inflammatory response of the rat hindpaw in response to carrageenan. The precursor of the compound was ineffective in the pharmacological tests.
Acetylcholine↗
Spermicidal effect of antagonists of platelet-activating factor.
A variety of antagonists of platelet-activating factor (PAF) have been examined for their ability to prevent pregnancy, by admixture with spermatozoa in vitro followed by insemination, or in vivo by administration to female rabbits. When the antagonists were added to the ejaculate at a concentration of 10(-4) M 30 minutes before insemination of the females, a significant failure of fertilization was seen only with CV-3988, U66985, and SRI 63-441--all structural analogs of PAF. Antagonists that were not structural analogs were not effective. All compounds to a lesser or greater extent caused some qualitative agglutination and loss of sperm motility, but these effects were not correlated with inhibition of fertilization. SRI 63-441 was the most effective compound and was subjected to further study. When given intravenously prior to ovulation (5 mg/kg at 1, 5, and 9 hours after the ovulating injection), no effect on fertilization was seen. If SRI 63-441 (40 mg in 0.5 ml aqueous solution) was instilled into the vagina 2 minutes before insemination, a highly significant reduction in the fertilization rate was achieved. It is concluded that these compounds act by an action on the sperm membrane rather than by direct PAF antagonism on spermatozoa.
Animals↗