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Results for “Quinolinium Compounds”

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At least 19 recordsLinked to original sources
PubMed1989

Inhibition of bovine heart mitochondrial and Paracoccus denitrificans NADH----ubiquinone reductase by dequalinium chloride and three structurally related quinolinium compounds.

1. Dequalinium chloride (DECA) and three related quinolinium compounds inhibit bovine heart mitochondrial and Paracoccus denitrificans electron transport activity, with inhibition localized between NADH and ubiquinone in both electron transport chains. 2. Structure-activity studies reveal that two quinolinium rings and a long bridging group are necessary for significant inhibition of reduction of artificial electron acceptors and coenzyme Q, whereas only one quinolinium ring and a long hydrocarbon side chain are required for significant inhibition of NADH oxidase activity. 3. Inhibition of coenzyme Q reduction by DECA is not reversed by dialysis. 4. Studies comparing DECA inhibition of rotenone-sensitive with rotenone-insensitive preparations indicate that DECA acts by a different inhibitory mechanism than rotenone on mammalian mitochondrial and P. denitrificans NADH----ubiquinone reductase.

Animals↗
PubMed2005

Symmetrical bis-quinolinium compounds: new human choline kinase inhibitors with antiproliferative activity against the HT-29 cell line.

Studies have been aimed at the establishment of structure-activity relationships that define choline kinase inhibitory and antiproliferative activities of 40 bisquinolinium compounds. These derivatives have electron-releasing groups at position 4 of the quinolinium ring. It is found that the enzymatic inhibition is closely related to the size of the linker, the 3,3'-biphenyl moiety being the most suitable. On the other hand, the antiproliferative activity against the HT-29 cancer cell line is less influenced by the linker type and by substituent R(4). The corresponding QSAR equation was obtained for the whole set of compounds for the antiproliferative activity, the electronic parameter sigma(R) of R(4), the molar refractivity of R(8), and the lipophilic parameters clog P and pi(linker). The most potent antiproliferative agent so far described is 40 for which an IC(50) = 0.45 microM was predicted by the QSAR equation, while its experimental value is IC(50) = 0.20 microM.

Biphenyl Compounds↗
PubMed1996

On the concept of a bivalent pharmacophore for SKCa channel blockers: synthesis, pharmacological testing, and radioligand binding studies on mono-, bis-, and tris-quinolinium compounds.

The dissociation equilibrium constants (Kd values) of dequalinium (2) and the monoquinolinium compounds 1a and 1b have been determined from competition equilibrium radioligand binding with [125I]apamin on rat brain synaptic plasma membranes (SPMs). Dequalinium binds to the channel with 2 orders of magnitude higher affinity than 1a or 1b, suggesting that both quinolinium groups are needed for potent and selective SKCa channel blockade. The trisquinolinium compound 3 (1,1'-[5-[4-(4- aminoquinolinium-1-yl)but-1-yl]non-4-en-1,9-diyl]-bis-(4- aminoquinolinium)) has been synthesized and tested for inhibition of the afterhyperpolarization of rat sympathetic neurones and on the binding assay. Compound 3 shows approximately one order of magnitude higher potency than 2, being the most potent non-peptidic SKCa channel blocker reported so far (Kd approximately 30 nM). The higher affinity of 3 compared with 2 may be due to direct binding of the third quinolinium group to the channel or may arise from a reduction of the unfavorable entropy of binding via an increase of the "local concentration" of quinolinium groups.

Animals↗
PubMed1982

DNA-binding specificity and RNA polymerase inhibitory activity of bis(aminoalkyl)anthraquinones and bis(methylthio)vinylquinolinium iodides.

The determination of DNA-binding specificities for a series of bis(methylthio)vinylquinolinium iodides and two bis (aminoalkyl)-anthraquinones was accomplished by spectral analysis, equilibrium dialysis, elevation of melting temperature, and inhibition of DNA function as a template for Escherichia coli RNA-polymerase transcription activity in vitro. Studies of complex formation were carried out by comparison of difference spectra of the compounds in the presence of native double-stranded DNA and separated-strand DNA. Base specificity of the interaction between DNA and the compounds was demonstrated for both series, particularly for the anthraquinones, for the guanine-cytosine base pair. Comparison of the difference spectra of the compounds in the presence of DNA with varied base-pair ratios showed a strong preference of the anthraquinones for the guanine-cytosine base pair, but the quinolinium compounds showed no preference. The linear-binding isotherm for the quinolinium compounds indicated one type of binding site, while two types of binding sites were apparent for the anthraquinones. Since only one anthraquinone was active in leukemia tests, factors other than DNA binding must account for the activity of the antileukemic derivative.

Animals↗
PubMed1995

Structure and interaction of inhibitors with the TEA/H+ exchanger of rabbit renal brush border membranes.

The renal secretion of organic cations (OCs) involves a carrier-mediated exchange of OC for H+ in the luminal membrane of proximal cells. To assess the influence of chemical structure on the interaction of potential substrates with this process we examined the effect of a series of quaternary ammonium compounds on the transport of the OC tetraethylammonium (TEA) in a preparation of isolated renal brush-border membrane vesicles. Apparent inhibitory potency varied over a factor of 10(4), as expressed in inhibitor coefficients (KiTEA) whose approximate values ranged from 0.5 microM to 5 mM. The poorest inhibitors of TEA/H+ exchange were those molecules with carboxyl or hydroxyl residues, whereas the addition of methylene groups to a parent molecule tended to increase inhibitory potency. A plot of apparent KiTEA versus calculated octanol:water partition coefficient (expressed in terms of a relative lipophilicity factor) showed a clear correlation between these two parameters, although there was considerable variability between apparent lipophilicity and KiTEA for molecules with very different parent structures. For select groups of molecules with similar parent structures (e.g., the n-tetraalkylammoniums or the 4-phenylpyridinium, 3-phenylpyridinium, and quinolinium compounds) the correlation between calculated lipophilicity and apparent KiTEA was more marked. However, even within these groups of closely related parent structures, there appeared to be subtle, but systematic, variations in inhibitory potency that may have been related to the influence of steric factors on the binding of inhibitors to the TEA/H+ exchanger. We conclude that the lipophilic nature of a quaternary ammonium compound represents the predominant factor in the binding to and subsequent inhibition of, luminal TEA/H+ exchange. Specific steric factors may influence the binding of substrate to the exchanger, but play a secondary role in this interaction.

Acridines↗
PubMed1992

Synthesis of cell-impermeable Cl-sensitive fluorescent indicators with improved sensitivity and optical properties.

Quinolinium compounds have been used as Cl-sensitive fluorescent indicators in cells and cell-free membrane fractions. To improve Cl sensitivity and for conjugation via nucleophilic reaction, the compounds 6-methoxy-N-(n-aminoalkyl)quinolinium bromide hydrochloride (AAQ) with alkyl chain lengths (n) of 2 (AEQ), 3 (APQ), and 4 (ABQ) were synthesized. AAQ was water soluble, fluorescent, and quenched by Cl. The Stern-Volmer constants (KCl) for quenching of protonated AEQ, APQ and ABQ by Cl were 354, 322, and 272 M-1, respectively, higher than KCl for 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ; 118 M-1). To eliminate pH-dependent fluorescence, 6-methoxy-N-(3-trimethylammoniumpropyl)quinolinium dibromide (TMAPQ) was synthesized (KCl, 310 M-1). To red shift fluorescence excitation and emission spectra, 6-phenyl-N-(3-trimethylammoniumpropyl)quinolinium dibromide (phenyl-TMAPQ) (emission 475 nm) and N-(3-trimethylammoniumpropyl)phenanthridinium dibromide (TMAPP) (excitation 380 nm) were synthesized. AEQ and ABQ were conjugated with neutral dextran activated by cyanogen bromide to give indicator-to-dextran mole ratios of 5 to 20. KCl values at pH 7.4 were 132 (AEQ-dextran) and 237 M-1 (ABQ-dextran). To construct a single molecule with Cl-sensitive and insensitive moieties, the bichromophores 6-methoxy-N-(n- dansylsulfonamidoalkyl)quinolinium with alkyl chains of two and four were synthesized. The new Cl-sensitive indicators were used for measurement of intracellular Cl activity and for the labeling of endocytic vesicles in 3T3 fibroblasts and T84 cells. Our results indicate that N-substitution of quinoline with positively charged moieties gives increased Cl sensitivity, and extension of ring conjugation gives indicators with red-shifted fluorescence spectra.

Cell Membrane Permeability↗
PubMed2000

Compounds that block both intermediate-conductance (IK(Ca)) and small-conductance (SK(Ca)) calcium-activated potassium channels.

1. Nine bis-quinolinyl and bis-quinolinium compounds related to dequalinium, and previously shown to block apamin-sensitive small conductance Ca(2+)-activated K(+) channels (SK(Ca)), have been tested for their inhibitory effects on actions mediated by intermediate conductance Ca(2+)-activated K(+) channels (IK(Ca)) in rabbit blood cells. 2. In most experiments, a K(+)-sensitive electrode was employed to monitor the IK(Ca)-mediated net loss of cell K(+) that followed the addition of the Ca(2+) ionophore A23187 (2 microM) to red cells suspended at an haematocrit of 1% in a low K(+) (0.12 - 0.17 mM) solution. The remainder used an optical method based on measuring the reduction in light transmission that occurred on applying A23187 (0.4 or 2 microM) to a very dilute suspension of red cells (haematocrit 0.02%). 3. Of the compounds tested, the most potent IK(Ca) blocker was 1,12 bis[(2-methylquinolin-4-yl)amino]dodecane (UCL 1407) which had an IC(50) of 0.85+/-0.06 microM (mean+/-s.d. mean). 4. The inhibitory action of UCL 1407 and its three most active congeners was characterized by (i) a Hill slope greater than unity, (ii) sensitivity to an increase in external [K(+)], and (iii) a time course of onset that suggested use-dependence. Also, the potency of the nonquaternary compounds tested increased with their predicted lipophilicity. These findings suggested that the IK(Ca) blocking action resembles that of cetiedil rather than of clotrimazole. 5. Some quaternized members of the series were also active. The most potent was the monoquaternary UCL 1440 ((1-[N-[1-(3, 5-dimethoxybenzyl)-2-methylquinolinium-4-yl]amino]-10-[N'-(2-me thylqu inolinium-4yl)amino] decane (trifluoroacetate) which had an IC(50) of 1.8+/-0.1 microM. The corresponding bisquaternary UCL 1438 (1, 10-bis[N-[1-(3,5-dimethoxybenzyl)-2-methylquinolinium-4-yl]amino] decane bis(trifluoroacetate) was almost as active (IC(50) 2.7+/-0.3 microM). 6. A bis-aminoquinolium cyclophane (UCL 1684) had little IK(Ca) blocking action despite its great potency at SK(Ca) channels (IC(50) 4.1+/-0.2 nM). 7. The main outcome is the identification of new intermediate-conductance Ca(2+)-activated K(+) channel blockers with a wide range of IK(Ca)/SK(Ca) selectivities.

Action Potentials↗
PubMed1994

Long-wavelength chloride-sensitive fluorescent indicators.

The goal of this study was to develop long-wavelength fluorescent Cl indicators that have improved optical properties over quinolinium compounds. A series of quaternized tricyclic heterocycles was screened. We found that N,N-dimethyl-9,9-bisacridinium (lucigenin) had very high halide sensitivity with Stern-Volmer constants for collisional quenching of 390 M-1 (Cl), 585 M-1 (Br), 750 M-1 (I), and 590 M-1 (SCN), much higher than those for the reference compound 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ) (118 M-1 (Cl)); lucigenin fluorescence was insensitive to phosphate, sulfate, and nitrate. Lucigenin fluorescence at 505 nm was excited with molar absorbances of 34,000 M-1 cm-1 (368 nm) and 7500 M-1 cm-1 (455 nm). To examine structure-activity relationships, five 9-substituted N-methylacridinium compounds were synthesized (9-amino, 9-carboxaldehyde, 9-carboxamide, 9-N,N-dimethylcarboxamide, and 9-methylcarboxylate), of which N-methylacridinium-9-carboxamide (MACA) had the best optical properties. MACA had excitation and emission maxima at 424 and 500 nm, and Stern-Volmer constants of 225 M-1 (Cl), 480 M-1 (Br), 550 M-1 (I), and 480 M-1 (SCN). The quantum yields of lucigenin and MACA were 0.6-0.7. The acridinium compounds are useful as Cl indicators in liposomes and membrane vesicles, but are not stable in cell cytoplasm.

3T3 Cells↗
PubMed1995

Synthesis and structure-activity relationships of dequalinium analogues as K+ channel blockers. Investigations on the role of the charged heterocycle.

Small conductance Ca(2+)-activated K+ (SKCa) channels occur in many cells but have been relatively little studied. Dequalinium, a bis-quinolinium compound, has recently been shown to be the most potent nonpeptidic blocker of this K+ channel subtype. This paper examines the importance of the quinolinium rings for blocking activity. Analogues of dequalinium were synthesised in which one quinolinium group was removed (1 and 2) or replaced by a triethylammonium group (3). They have been assayed in vitro for their ability to block the after-hyperpolarization (mediated by the opening of SKCa channels) that follows the action potential in rat sympathetic neurones. The compound having one quinolinium and one triethylammonium group (3) showed reduced activity, and it is suggested that the stronger binding to the channel of the quinolinium relative to the triethylammonium group may be related to differences in their electrostatic potential energy maps. Two monoquaternary compounds (1 and 2) were tested, but they exhibited a different pharmacological profile that did not allow definite conclusions to be drawn concerning their potency as blockers of the SKCa channel. Replacement of both quinolinium groups by pyridinium, acridinium, isoquinolinium, or benzimidazolium reduced but did not abolish activity. These results show that compounds having a number of different heterocyclic cations are capable of blocking the SKCa channel. However, among the heterocycles studied, quinoline is optimal. Furthermore, charge delocalization seems to be important: the higher the degree of delocalization the more potent the compound.

Animals↗
PubMed2003

Influence of molecular structure on substrate binding to the human organic cation transporter, hOCT1.

Organic cation transporters play a critical role in the elimination of therapeutic compounds in the liver and the kidney. We used computational quantitative structure activity approaches to predict molecular features that influence interaction with the human ortholog of the organic cation transporter (hOCT1). [(3)H]tetraethylammonium uptake in HeLa cells stably expressing hOCT1 was inhibited to varying extents by a diverse set of 30 molecules. A subset of 22 of these was used to produce, using Catalyst, a pharmacophore that consisted of three hydrophobic features and a positive ionizable feature. The correlation coefficient of observed versus predicted IC(50) was 0.86 for this training set, which was superior to calculated logP alone (r = 0.73) as a predictor of hOCT1 inhibition. A descriptor-based quantitative structure-activity relationship study using Cerius(2) resulted in an equation relating five molecular descriptors to log IC(50) with a correlation coefficient of 0.95. Furthermore, a group of phenylpyridinium and quinolinium compounds were used to investigate the spatial limitations of the hOCT1 binding site. The affinity for hOCT was higher for 4-phenylpyridiniums > 3-phenylpyridiniums > quinolinium, indicating that substrate affinity was influenced by the distribution of hydrophobic mass. In addition, supraplanar hydrophobic mass was found to increase the affinity for binding hOCT1. These results indicate how a combination of computational and in vitro approaches may yield insight into the binding affinity of transporters and may be applicable to predicting these properties for new therapeutics.

Computational Biology↗
PubMed1995

Platelet activating factor inhibition reduces lung injury after cardiopulmonary bypass.

Because cardiopulmonary bypass (CPB) produces a diffuse inflammatory reaction that may injure multiple organs and complicate cardiac surgical procedures, we examined the use of a competitive inhibitor of platelet activating factor (SDZ HUL-412) in a porcine model of CPB as a means to ameliorate pulmonary injury after CPB. Thirteen pigs (35 to 40 kg) underwent CPB at 28 degrees C for 2 hours, followed by 2 hours of observation. Group I (n = 6) received SDZ HUL-412 (a quinolinium compound) intravenously (3 mg/kg loading dose and 2 mg.kg-1.h-1 continuous infusion) starting before sternotomy. Group II (n = 7) received a saline vehicle. Peak airway pressure, pulmonary arterial pressure, left atrial pressure, and arterial blood gases were measured and flow cytometry evaluated surface expression of adhesion molecule subunit CD18 on circulating neutrophils. Pulmonary function was significantly improved in group I. Fifteen minutes after CPB, dynamic lung compliance in group I was 91% +/- 12% of baseline versus 49% +/- 5.2% in group II (p = 0.06 by analysis of variance). After CPB, the arterial oxygen pressure was also significantly better in group I than in group II (425 +/- 61 versus 234 +/- 76 mm Hg) (p < 0.05). The rise in pulmonary vascular resistance after CPB was less in group I (p < 0.05) (323 +/- 55 to 553 +/- 106 dynes.s.cm-5) than in group II (531 +/- 177 to 884 +/- 419 dynes.s.cm-5) at the end of the observation period. CD18 up-regulation increased similarly in the two groups during CPB.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed2006

Proton-transfer and non-transfer in compounds of quinoline and quinaldic acid with L-tartaric acid.

The structures of two compounds of L-tartaric acid with quinoline, viz. the proton-transfer compound quinolinium hydrogen (2R,3R)-tartrate monohydrate, C9H8N+.C4H5O6-.H2O, (I), and the anhydrous non-proton-transfer adduct with quinaldic acid, bis(quinolinium-2-carboxylate) (2R,3R)-tartaric acid, 2C10H7NO2.C4H6O6, (II), have been determined at 130 K. Compound (I) has a three-dimensional honeycomb substructure formed from head-to-tail hydrogen-bonded hydrogen tartrate anions and water molecules. The stacks of pi-bonded quinolinium cations are accommodated within the channels and are hydrogen bonded to it peripherally. Compound (II) has a two-dimensional network structure based on pseudo-centrosymmetric head-to-tail hydrogen-bonded cyclic dimers comprising zwitterionic quinaldic acid species which are interlinked by tartaric acid molecules.

Journal Article↗