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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↗
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↗
PubMed1991

[Rough sets theory in the analysis of structure-activity relationships of quaternary quinolinium- and isoquinolinium compounds].

Relationship between chemical structure and antimicrobial activity of 72 quaternary quinolinium and isoquinolinium compounds is analyzed using the theory of rough sets. The compounds are described by 11 attributes concerning structure and are divided into 3 classes of activity. The description builds up on information system. Using the rough sets approach a smallest set of attributes significant for a high quality of classification has been found. A decision algorithm has been driven from the information system showing up important relations between structure and activity. This may be helpful in supporting decisions concerning synthesis of new antimicrobial compounds.

4-Quinolones↗
PubMed1992

Reversible or irreversible modification of [3H]PAF binding on rabbit platelet membranes differentiates various PAF receptor antagonists.

[3H]Platelet-activating factor (PAF) binding to rabbit platelet membranes was examined before and after 20 min preincubation at 25 degrees C in the presence of PAF, lysoPAF, or of five different PAF receptor antagonists (L 652731, BN 52021, WEB 2086, BN 52111 and BN 52115). When platelet membranes were not washed after preincubation with PAF or PAF antagonists, no significant specific binding of [3H]PAF was observed, which suggests full occupancy of the binding sites. When membranes were extensively washed, full recovery of specific [3H]PAF binding was attained with L 652731 and partial recoveries (60%, 55% and 30%) were reached with BN 52021, WEB 2086 and PAF, respectively; no recovery was seen with the dioxolanes BN 52111 and BN 52115. Scatchard analysis of the binding data indicated that no significant change in the dissociation constant (Kd) and maximum number of binding sites (Bmax) occurred after preincubation of platelet membrane with L 652731, whereas a reduction of Bmax was observed when PAF and BN 52021 were measured. When platelet membranes were preincubated with WEB 2086, Bmax and Kd significantly increased. The data suggest differing binding properties for PAF and the PAF antagonists. Some of the PAF antagonists may tightly bind to the PAF receptor site(s) and/or irreversibly modify or downregulate PAF recognition sites. Our results also suggest that the interaction of PAF receptor antagonists with PAF receptor can be divided into at least two components, namely a reversible component and an irreversible one.

Animals↗
PubMed1978

Prophylactic activity in rodents of trypanocides complexed with dextran.

The prophylactic activity of prepared complexes of each of several trypanocidal drugs with dextran sulphate (M.W. 5 X 10(5)) was determined in rodents at the same time as that of the corresponding uncomplexed drug, and also the suramin complex in some cases. All the dextran complexes tested showed some degree of enhanced prophylaxis over the uncomplexed drug but in most cases a significant extension of prophylaxis was demonstrated only at dose levels well in excess of those used in the field. The dextran complex of isometamidium, however, showed very considerable enhancement effects over a range of dose levels. An amount of this complex containing an equivalent of the therapeutic dose of uncomplexed drug extended the period of effective prophylaxis by several months in both rats and mice. The suramin complex of isometamidium, on the other hand, was almost invariably less effective than the uncomplexed drug.

Animals↗
PubMed1991

Inhibition of immune complex-induced enteropathy by three different platelet-activating factor receptor antagonists.

We previously showed that intravenous injection of rat anti-BSA-BSA complexes (IC) prepared in 5x antigen excess rapidly induced a striate pattern of serosal (to mucosal) hemorrhage and vascular congestion throughout the small intestine of the Sprague-Dawley rat. In this study, we tested the effect of three different platelet-activating factor (PAF) receptor antagonists on the development of lesions. L-652,731, a synthetic derivative of kadsurenone (at doses of 1.3-2.7 mg/kg), SRI 63-675, a substituted quinolinium compound (6.7-15 mg/kg), and WEB 2086, a thienotriazolodiazepine (5-25 mg/kg) were each capable of completely or partially inhibiting IC-induced enteropathy in the majority of animals tested. Pretreatment with WEB 2086 prevented IC-induced hemoconcentration but not neutropenia. The antagonists did not lower the level of blood complement nor interfere with the fall in complement induced by administration of IC. The ability of PAF receptor antagonists to completely or partially inhibit IC-induced small intestinal lesions suggests that endogenous PAF is a major mediator of IC-induced enteropathy.

Animals↗
PubMed1979

Effect of potential cytostatic and immune modulating chemicals on the plasma membrane of red blood cells (RBC) as revealed by osmotic hemolysis, cell electrophoresis and scanning electron microscopy (SEM).

The influence on red blood cells (RBC) of two cancerostatic-(ZIMET 3106 and ZIMET 3393) and two immunomodulating agents (ZIMET 3164 and ZIMET 86/76) administered subcutaneously, or intraperitoneally in case of the radiolabelled N-mustard compounds, to mice, was studied by means of measurements of the radiolabelled compounds in blood, by cell electrophoresis, filipin-induced hemolysis of pretreated RBC and by scanning electronmicroscopy. The portion of doses applied which binds to RBC-surface decreases in the sequence of ZIMET 3106, ZIMET 3164, ZIMET 3393 and ZIMET 86/76. However, the highest reduction of the electrophoretic mobility and protection from filipin-induced hemolysis of pretreated RBC was found with ZIMET 3164. In both tests ZIMET 86/76 proved to be ineffective. These findings are in good agreement with the modifications demonstrated in pretreated RBC after filipin-induced hemolysis by means of SEM. The results presented point to a N-mustard specific interaction between the cholesterol of the membrane and/or other membrane constituents. However, these fundamental differences found in binding affinity, surface-charges and membrane interactions caused by the chemically similar compounds cannot be attributed merely to the N-mustard group.

Animals↗
PubMed1987

Interaction of the nonintercalative antitumour drugs SN-6999 and SN-18071 with DNA: influence of ligand structure on the binding specificity.

Binding to DNA's of the non-intercalative ligands SN-6999 and SN-18071 has been studied by means of circular dichroism, UV absorption, thermal melting and for SN-6999 by viscosity measurements. Both antitumour drugs show a preference for dA.dT rich DNA's, but the base pair selectivity of SN-18071 is lower as indicated by some affinity to dG.dC containing duplex DNA. The dA.dT base pair specificity of SN-6999 is comparable to that of netropsin. It forms very stable complexes with dA.dT containing duplex DNA and competes with netropsin binding on DNA. The ligands SN-18071 and pentamidine are totally released from their complexes with poly(dA-dT).poly(dA-dT) by competitive netropsin binding. The results demonstrate that hydrogen bonding capacity of the ligand in addition to other factors strongly contribute to the base sequence specificity in the recognition process of the ligand with DNA. A binding model of SN-6999 with five dA.dT pairs in the minor groove of B-DNA is suggested.

Antineoplastic Agents↗
PubMed1991

Dopaminergic neurotoxicity in vivo and inhibition of mitochondrial respiration in vitro by possible endogenous pyridinium-like substances.

Elucidation of the mechanism(s) by which 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP+) cause parkinsonism in humans and other primates has prompted consideration of possible endogenous MPTP/MPP(+)-like neurotoxins in the etiology of idiopathic Parkinson's disease. Here we examined inhibition of mitochondrial respiration in vitro and neurotoxicity in rats in vivo produced by beta-carbolinium compounds that are presumed to form following Pictet-Spengler cyclization of serotonin. We also evaluated N-methylisoquinolinium, a putative endogenous neurotoxin, in the same manner. The latter compound exhibited MPP(+)-like mitochondrial respiratory inhibition, whereas the beta-carbolinium compounds, although more potent inhibitors of electron transport, exhibited weak accumulation-dependent enhancement of inhibition in intact mitochondria. It is interesting that the beta-carbolinium compounds inhibited succinate- as well as glutamate-supported respiration, and are best described as inhibitor-uncouplers. The results of partitioning experiments suggest that both the low accumulation potential and the inhibition of succinate respiration may be a consequence of the beta-carboliniums being in equilibrium with neutral "anhydro" bases. Relative to MPP+, all compounds tested had weak dopaminergic uptake activity in vitro and weak dopaminergic toxicity in vivo, consistent with other findings of relatively low neurotoxic potential for presumed endogenous pyridiniums.

1-Methyl-4-phenylpyridinium↗
PubMedDate not supplied

Action of platelet-activating factor (PAF) antagonists on the bronchopulmonary effects of PAF in the guinea-pig.

Intravenous injection of BN 52021 in anesthetized guinea-pigs, 5 min before challenge, inhibited in a dose-dependent fashion with an IC50 of 0.90 mg/kg the bronchoconstriction induced by PAF (60 ng/kg i.v.). However, BN 52021 did not prevent the leukopenia following PAF injection but significantly inhibited the thrombocytopenia induced by PAF. The dioxolan compound, BN 52111, dose-dependently reduced the bronchoconstriction (IC50 = 0.27 mg/kg) and at doses higher than 1 mg/kg partially antagonized the decrease in the number of circulating platelets and leukocytes induced by PAF. BN 52115 also markedly inhibited the bronchoconstriction (IC50 = 0.36 mg/kg) as well as the thrombocytopenia induced by PAF, but was without significant effect on the leukopenia. These results demonstrate that the two dioxolan compounds, BN 52111 and BN 52115, are more potent than BN 52021 in inhibiting the in vivo bronchopulmonary alterations induced by PAF. Since these alterations are related to the activation of platelets by the autacoid, these blood elements are probably the targets of BN 52111 and BN 52115. Injection of PAF (10 and 100 ng) via the pulmonary artery of ventilated and perfused guinea-pig lungs induced dose-dependent increases in pulmonary inflation pressure (PIP) and pulmonary perfusion pressure (PPP), associated with a dose-dependent release of thromboxane B2 (TxB2). Addition of BN 52021, BN 52111 or BN 52115 (0.1, 1 or 10 microM) to the perfusion medium, 15 min before challenge, dose-dependently inhibited the bronchopulmonary effects of PAF. Although BN 52111 was the more potent in inhibiting the PAF-induced increase in PIP, BN 52021 was the more active with respect to the PAF-evoked generation of TxB2, suggesting that the two phenomena are not directly related.

Animals↗
PubMed1989

Desensitization of platelet-activating factor-stimulated protein phosphorylation in platelets.

Treatment of 32P-labeled rabbit platelets with platelet-activating factor (PAF) caused a time- and dose-dependent phosphorylation of several proteins including five major phosphorylated proteins with apparent molecular weights of 20,000, 35,000, 40,000, 65,000, and 150,000. Both PAF and thrombin caused a rapid increase followed by a decrease in phosphorylation of proteins, indicating the occurrence of a phosphorylation-dephosphorylation process. Four separate PAF receptor antagonists, CV-3988, CV-6209, SRI-63-441, and SRI-63-675 drastically reduced the PAF-stimulated protein phosphorylation. The order of potency was SRI-63675 greater than SRI-63441 greater than or equal to CV-6209 greater than CV-3988. These antagonists had no effect on thrombin-stimulated protein phosphorylation. Pretreatment of platelets with PAF (0.1 nM) completely abolished any further protein phosphorylation by the same concentration of PAF. PAF pretreatment shifted the dose response of protein phosphorylation by about 2 log units, to the right. When platelets were treated with PAF (10 nM) for 10 min, this abolished phosphorylation of proteins by any concentration of PAF. These studies indicated a homologous desensitization of protein phosphorylation. Interestingly, PAF-pretreated platelets still exhibited phosphorylation of proteins by thrombin. On the other hand, a lack of protein phosphorylation by PAF or thrombin was observed in platelets preexposed to thrombin and this demonstrated a heterologous desensitization. It is concluded that phosphorylation of proteins by PAF is a PAF receptor-coupled event and that this process is desensitized in platelets preexposed to PAF. The fact that both the activation of phosphoinositide-specific phospholipase C and the phosphorylation of proteins are desensitized in PAF-pretreated platelets suggests that a close "regulatory" intercommunication between these processes exists.

Animals↗
PubMed1989

Antagonism of platelet activating factor receptor binding and stimulated phosphoinositide-specific phospholipase C in rabbit platelets.

The objective of this study was to establish whether binding of platelet activating factor (PAF) to its receptor was integral to the stimulation of phosphoinositide-specific phospholipase C (PLC) in rabbit platelets. Saturation binding curves for [3H]PAF indicated that the PAF receptor has a dissociation constant (KD) of 28.72 nM. In comparison, PAF-stimulated PLC activity, as monitored by [3H]inositol triphosphate production, increased at lower concentrations and had an half-maximal effective concentration (EC50) value of 1.5 nM. Unlabeled PAF inhibited [3H]PAF binding competitively and demonstrated two binding sites, a high affinity site with an inhibitory constant (Ki) of 2.65 nM and a low affinity site with a Ki of 0.80 microM. The inhibitory effects of four PAF antagonists, CV-3988, CV-6209, SRI 63-441 and SRI 63-675 on the binding of [3H]PAF were compared to the effects of the antagonists on PAF-stimulated PLC activity. The four antagonists inhibited [3H]PAF binding almost completely whereas their ability to inhibit PAF-stimulated PLC activity varied. CV-3988, SRI 63-441 and SRI 63-675 had half-maximal inhibitory concentration (IC50) values of 0.28, 0.78 and 0.42 microM, respectively, whereas CV-6209 was more potent at inhibiting [3H]PAF binding (IC50 = 7.73 nM). The SRI 63-441 and SRI 63-675 inhibited PLC totally with an IC50 value of 0.78 and 1.27 microM, respectively. The CV-3988 and CV-6209 showed a maximal PLC inhibition of about 45% with "apparent IC50" values of 1.05 and 0.17 microM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗