Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Onium Compounds”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 235 records · Page 13Linked to original sources
PubMed1997

The thromboxane A2 and K(ATP) channel antagonist actions of a series of sulphonylurea derivatives in the pig coronary artery.

The ability of a series of sulphonylurea derivatives to antagonise the vasorelaxant actions of the ATP-dependent K+ channel (K(ATP)) opener, levcromakalim, and the vasoconstrictor responses of the thromboxane A2 mimetic, U46619, were assessed in the pig coronary artery. The sulphonylurea derivatives of glibenclamide caused a rightward shift in the concentration-vasorelaxant response curve obtained to levcromakalim in arterial segments pre-constricted with acetylcholine (0.5 microM). From these shifts pK(B) were calculated to estimate the potency of these compounds as levcromakalim antagonists. Similarly U46619 concentration-vasoconstrictor responses curves were constructed in the absence and in the presence of a sulphonylurea derivative and pK(B) values calculated. Regression analysis of pK(B) values showed that there was a significant correlation between the potency of these compounds in the two systems studied indicating similar structure-activity relationships apply in both cases. That sulphonylureas regulate K(ATP) channel opening is well known and they do so through a specific receptor associated with the channel. The results obtained in this study may indicate that a sulphonylurea receptor may also be associated with thromboxane A2 excitation-contraction coupling.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2006

Accumulation of lipophilic dications by mitochondria and cells.

Lipophilic monocations can pass through phospholipid bilayers and accumulate in negatively-charged compartments such as the mitochondrial matrix, driven by the membrane potential. This property is used to visualize mitochondria, to deliver therapeutic molecules to mitochondria and to measure the membrane potential. In theory, lipophilic dications have a number of advantages over monocations for these tasks, as the double charge should lead to a far greater and more selective uptake by mitochondria, increasing their therapeutic potential. However, the double charge might also limit the movement of lipophilic dications through phospholipid bilayers and little is known about their interaction with mitochondria. To see whether lipophilic dications could be taken up by mitochondria and cells, we made a series of bistriphenylphosphonium cations comprising two triphenylphosphonium moieties linked by a 2-, 4-, 5-, 6- or 10-carbon methylene bridge. The 5-, 6- and 10-carbon dications were taken up by energized mitochondria, whereas the 2- and 4-carbon dications were not. The accumulation of the dication was greater than that of the monocation methyltriphenylphosphonium. However, the uptake of dications was only described by the Nernst equation at low levels of accumulation, and beyond a threshold membrane potential of 90-100 mV there was negligible increase in dication uptake. Interestingly, the 5- and 6-carbon dications were not accumulated by cells, due to lack of permeation through the plasma membrane. These findings indicate that conjugating compounds to dications offers only a minor increase over monocations in delivery to mitochondria. Instead, this suggests that it may be possible to form dications within mitochondria that then remain within the cell.

Adenosine Triphosphate↗
PubMed2001

The ostensible paradox of multidrug recognition.

The ability of multidrug-efflux transporters to recognize scores of dissimilar organic compounds has always been considered paradoxical because of its apparent contradiction to some of the basic dogmas of biochemistry. In order to understand, at least in principle, how a protein can recognize multiple compounds, we analysed the transcriptional regulator of the Bacillus subtilis multidrug transporter Bmr. This regulator, BmrR, binds multiple dissimilar hydrophobic cations and, by activating expression of the Bmr transporter, causes their expulsion from the cell. Crystallographic analysis of the complexes of the inducer-binding domain of BmrR with some of its inducers revealed that ligands penetrate the hydrophobic core of the protein, where they form multiple van der Waals and stacking interactions with hydrophobic amino acids and an electrostatic bond with the buried glutamate. Mutational analysis of the binding site suggests that each ligand forms a unique set of atomic contacts with the protein: each tested mutation exerted disparate effects on the binding of different ligands. The example of BmrR demonstrates that a protein can bind multiple hydrophobic compounds with micromolar affinities by using only electrostatic and hydrophobic interactions. Its ligand specificity can be further broadened by the flexibility of the binding site. It appears, therefore, that the commonly expressed fascination with the relaxed substrate specificity of multidrug transporters is misdirected and originates from an almost exclusive familiarity with the more sophisticated processes of specific molecular recognition that predominate among proteins analyzed to date.

Bacillus subtilis↗
PubMed2001

Development of lipophilic cations as therapies for disorders due to mitochondrial dysfunction.

Mitochondrial dysfunction causes or exacerbates a number of diseases. These include genetic disorders such as Friedreich's ataxia where the primary lesion is a defect in a nuclear gene and those diseases caused by mutations to mitochondrial DNA. Mitochondrial damage also contributes to neurodegenerative diseases, diabetes and ischaemia-reperfusion injury. Drug therapies to prevent or alleviate mitochondrial dysfunction use redox active compounds, anti-oxidants or mitochondrial co-factors, however, their effectiveness is limited. A promising approach to increase the selectivity and potency of these compounds is to modify them so that they concentrate within mitochondria. This can be done by incorporating a lipophilic cation which causes the molecules to concentrate several hundred-fold in mitochondria, driven by the membrane potential across the inner membrane. As lipophilic cations cross biological membranes easily, they can be delivered to mitochondria of the heart, brain and skeletal muscle, the organs most affected by mitochondrial damage. Mitochondria-targeted lipophilic cations may lead to improved therapies for diseases involving mitochondrial dysfunction.

Animals↗
PubMed1991

Identification of a superoxide-generating NADPH oxidase system in human fibroblasts.

Human fibroblasts have the capacity to release superoxide radicals upon stimulation of an electron transport system similar to the NADPH oxidase of leukocytes. Two components of the NADPH oxidase system, (1) a flavoprotein of 45 kDa which binds diphenylene iodonium (a compound described as a specific inhibitor of the leukocyte NADPH oxidase), and (2) a low-potential cytochrome b, are present in fibroblast membranes. Fibroblasts exhibit these compounds at lower concentrations than do polymorphonuclear leukocytes or B-lymphocytes. The superoxide-generating system is rather uniformly associated with the outer cell membrane, as shown by light and electron microscopy. Superoxide release upon stimulation with various agents was prevented by the addition of micromolar concentrations of diphenylene iodonium, making an NADPH oxidase a likely source.

Calcimycin↗
PubMed1997

MdfA, an Escherichia coli multidrug resistance protein with an extraordinarily broad spectrum of drug recognition.

Multidrug resistance (MDR) translocators recently identified in bacteria constitute an excellent model system for studying the MDR phenomenon and its clinical relevance. Here we describe the identification and characterization of an unusual MDR gene (mdfA) from Escherichia coli. mdfA encodes a putative membrane protein (MdfA) of 410 amino acid residues which belongs to the major facilitator superfamily of transport proteins. Cells expressing MdfA from a multicopy plasmid are substantially more resistant to a diverse group of cationic or zwitterionic lipophilic compounds such as ethidium bromide, tetraphenylphosphonium, rhodamine, daunomycin, benzalkonium, rifampin, tetracycline, and puromycin. Surprisingly, however, MdfA also confers resistance to chemically unrelated, clinically important antibiotics such as chloramphenicol, erythromycin, and certain aminoglycosides and fluoroquinolones. Transport experiments with an E. coli strain lacking F1-F0 proton ATPase activity indicate that MdfA is a multidrug transporter that is driven by the proton electrochemical gradient.

Amino Acid Sequence↗
PubMed2000

Non-depolarizing neuromuscular blocking activity of bisquaternary amino di- and tripeptide derivatives.

Herein we describe the synthesis of novel di- and tripeptide derivatives with two quaternary nitrogen groups attached and the biological testing of these compounds for neuromuscular blocking (NMB) activity in vitro and in vivo. The short peptide scaffold was selected because it offers potential for desired distance between the two pharmacophoric quaternary nitrogen groups, short duration of action, straightforward synthesis, and compatibility with an injectable formulation. From a small series of compounds 20c,e are identified as effective non-depolarizing NMB agents in vitro and in vivo in anesthetized cats and Rhesus monkeys with potencies similar to those of the clinical reference compounds rocuronium (4) and suxamethonium (2) (monkey ED(90) = 0.68, 0.23, 0.16, 5.04 micromol/kg, respectively). These new peptide derivatives 20c,e have similar potency and onset time but longer duration and slower recovery than the clinically used reference compounds. The structure-activity relationships described for this chemical series lead to the conclusion that the di- or tripeptide fragment can be regarded as an alternative template to the steroid or aliphatic ester of previously reported NMBs and within this tripeptide-derived series clog P correlates well with in vitro NMB activity.

Amines↗
PubMed1995

An NADPH oxidase superoxide-generating system in the rabbit aorta.

Superoxide anion can modulate vascular smooth muscle tone and potentially affect the growth response in vascular disease. The present studies were undertaken to characterize the source of superoxide in rabbit aorta. Rings of aorta (5 mm) were incubated in physiological salt solution (PSS) for 30 min at 37 degrees C in the presence of 10 mM diethyldithiocarbamate (DDC) with or without inhibitors of superoxide-generating systems. Rings were then placed in PSS containing 250 microM lucigenin at 37 degrees C in the presence or absence of inhibitors, and changes in amounts of superoxide were determined by measuring chemiluminescence (units). The inhibitors of xanthine oxidase, oxypurinol (300 microM), and of mitochondrial NADH dehydrogenase, rotenone (50 microM), had no significant effect on superoxide levels. An inhibitor of NADPH oxidase, iodonium thiophen, caused a concentration-dependent inhibition of superoxide anion (12.49 +/- 1.48 vs 5.27 +/- 1.81 and 2.30 +/- 0.36 units, control vs 7 microM and 70 microM iodonium thiopen, respectively). A structurally related iodonium compound, diphenyleneiodonium (20 microM), caused a 78% reduction in basal and DDC-evoked superoxide levels. In the presence or absence of DDC, exogenous administration of NADPH (10 microM-1 mM), but not NADP (1 mM), elicited a concentration-dependent rise in superoxide levels that was inhibited by iodonium thiophen. Particulate fractions of whole aortic tissue exhibited NADPH-dependent superoxide production that was inhibited by 1 microM diphenyleneiodonium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Determination of bismuth in pharmaceutical products using methyltriphenylphosphonium bromide as a molecular probe by resonance light scattering technique.

A method for the determination of bismuth in pharmaceutical products using methyltriphenylphosphonium bromide as a molecular probe based on the resonance light scattering (RLS) technique was developed. In the presence of Tween-20, bismuth reacts with a large excess of I(-) to form [BiI(4)](-), which further reacts with methyltriphenylphosphonium bromide (MTPB) to form an ion-association compound. This resulted in a significant enhancement of RLS intensity and the appearance of the corresponding RLS spectral characteristics. The enhanced RLS intensity was directly proportional to the concentration of Bi(III) in the range of 0.001-1.50 microg/ml for the system. The detection limit was 0.98 ng/ml. The characteristics of RLS spectra of the complex, the optimum conditions and the influencing factors were investigated. The method has high selectivity and was applied to the determination of Bi(III) in pharmaceutical products with satisfactory results, which were in agreement with those of the official method and atomic absorbance spectrometry (AAS).

Bismuth↗
PubMed1999

Does diphenylene iodonium chloride have any effect on the O2- -generating step of plant peroxidases?

The O2*- -generating step of plant peroxidases during their catalytic cycle is represented by the decay of compound III (CoIII) into ferriperoxidase, which most likely involves the dissociation of a ferric-O2*- complex to yield the ferric form of the enzyme and O2*-. Diphenylene iodonium chloride (DPI), at 50-100 microM, does not significantly enhance the stability of CoIII of peroxidase, as judged by the values of k(decay), and therefore, DPI appears to have no effect on the O2*- -generating step of plant peroxidases. From these results, it is concluded that caution should be exercised when considering peroxidase as a possible enzyme target of O2*- -mediated plant physiological processes sensitive to DPI inhibition.

Electrophoresis, Polyacrylamide Gel↗
PubMed1975

Carcinogenesis.

An examination has been made of the major chemicals which are known to be carcinogenic, either in animals or in humans. As a result, a generalized type of chemical property seems to be a prerequisite for the carcinogenic activity. In most cases, this is some kind of reactive electrophilic intermediate produced directly from the carcinogen or from one of its immediate metabolites. This electrophilic reagent is generally a positively charged ion of some kind. In the case of the hydrocarbons it seems to be an incipient carbonium ion; in the case of nitrogen compounds, it is a corresponding nitronium ion. There are a number of possible substrate materials (nucleophilic) in a cells, but the dominant one which has been suspected is the nucleic acid component, either the DNA or the RNA. The bases of these materials all have extra pi electrons susceptible to attach by the electrophiles of the carcinogen. Such a modification, particularly of the DNA, could lead to either major or minor changes in the genetic composition of the cell. Minor changes are usually rectifiable or are not visible, and this would include a large variety of point mutations.

2-Acetylaminofluorene↗
PubMed1988

Dimethylsulfonium and thiolanium analogues of the muscarinic agent oxotremorine.

Dimethylsulfonium (6a and 6b) and thiolanium analogues (7a and 7b) of oxotremorine were synthesized and found to be potent muscarinic agents in vivo and vitro. Compound 6a exceeded oxotremorine in potency. Their affinities for muscarinic receptors in the guinea pig ileum and urinary bladder, estimated pharmacologically, were higher than those of the corresponding trimethylammonium (8a and 8b) and N-methylpyrrolidinium compounds (9a and 9b). However, the new compounds had lower intrinsic efficacies than their quaternary ammonium analogues. The compounds also had high affinity for central muscarinic receptors as measured by displacement of specifically bound (-)-[3H]-N-methylscopolamine from homogenates of the rat cerebral cortex. Half-maximal occupation of cortical muscarinic receptors by 6a, 6b, 7a, and 7b was achieved at concentrations of 0.8, 5.4, 0.3, and 3.3 microM, respectively. The competition curves of 6a, 6b, and 7a were adequately described by a two-site binding equation. The ratio of low- and high-affinity dissociation constants agreed with relative efficacy estimated on the ileum. The thiolanium salt 7a was a fairly potent nicotinic agent on the frog rectus abdominis.

Animals↗
PubMed1986

The mechanism by which cyclopiazonic acid potentiates accumulation of tetraphenylphosphonium in cultured renal epithelial cells.

Cyclopiazonic acid (CPA), a fungal metabolite produced by Aspergillus and Penicillium, potentiated the accumulation of the quaternary cation tetraphenylphosphonium (TPP+) in cultured pig renal epithelial cells. This is the first report of a natural product mediating the tight and apparently nonsaturable binding of a membrane potential probe to subcellular compartments. The potentiated TPP+ accumulation was dose dependent, nonsaturable, and not a result of hyperpolarization across the plasma membrane. Cyclopiazonic acid-potentiated accumulation was completely inhibited by the protonophore carbonylcyanide-m-chlorophenylhydrazone (CCCP). Dinitrophenol (DNP), tetrahexylammonium (THA), and n-ethylmaleimide (NEM) were also effective inhibitors of CPA-potentiated TPP+ accumulation. Although CPA-potentiated TPP+ uptake appeared to be energy dependent, TPP+ efflux (in the presence of CCCP) from CPA-treated cells was incomplete and most of the TPP+ accumulated in the presence of CPA was tightly bound. Dicyclohexylcarbodiimide (DCC), verapamil, and monensin also stimulated TPP+ accumulation, but the TPP+ which accumulated in the presence of these compounds was not tightly bound. As with controls, fractionation of cells which had accumulated TPP+ in the presence of DCC, verapamil, or monensin always resulted in near complete recovery (greater than 93%) of the TPP+ in the cytosolic fraction, whereas with CPA, greater than 88% of the TPP+ was recovered noncovalently bound in the plasma membrane and mitochondrial fractions. These results are consistent with the hypothesis that CPA-potentiated TPP+ accumulation is a result of potentiated partitioning of TPP+ into the plasma membranes and mitochondria of LLC-PK1 cells.

Animals↗
PubMed1997

Effect of butylhydroxytoluene and related compounds on permeability of the inner mitochondrial membrane.

Mitochondrial inner membrane contains a latent pore (PTP) that when opened uncouples mitochondrial energy transduction and allows rapid equilibration of low-molecular-weight solutes between the matrix and exterior. Based on sensitivity of the PTP to well-known free radical scavenger butylhydroxytoluene (BHT), it has been proposed that increased steady-state level of oxygen radicals, and subsequent radical attack of proteins and lipids, is a central event in activation of this pore (Novgorodov et al., J. Bioenerg. Biomembr. 19, 191-202, 1987; Carbonera and Azzone, Biochim. Biophys. Acta 943, 245-255, 1988). Present studies revealed that DBT, a derivative of BHT devoid of radical scavenging activity, exerts an analogous effect on the permeability of the inner membrane. Inhibition of the Ca2+-induced PTP opening is essentially complete at dose range of 50-60 nmol/mg protein with IC50 values of about 32 and 23 nmol/mg protein for DBT and BHT, respectively. Electron microscopy and osmotic experiments utilizing polyethylene glycols with different Stokes radii showed that the apparent lack of inhibition seen at high concentrations of these compounds results from cyclosporin A- and Ca2+-insensitive pore formation in the inner membrane. Experiments employing antioxidants with similar structure but dissimilar hydrophobicity provided evidence for localization of the antioxidant binding sites within the hydrophobic zone of the inner membrane or in the matrix space. The data obtained do not refute the notion that oxygen radicals modulate the PTP, but rather indicate that BHT operates independently of its free radical scavenging activity. Overall, the sensitivity to BHT and other antioxidants is not always a reliable criterion for the involvement of free radical reactions in the processes under study.

Animals↗
PubMed2001

Understanding channel blocking in the nicotinic acetylcholine receptor.

Ion-channel blockers are molecules that obstruct the path used by ions to cross the membrane through a protein channel. Many of these are local anesthetics, toxins or drugs of abuse, and the knowledge of their mechanism of action at the atomic level is an important step towards the development of new compounds on a structural basis. A molecular model of the transmembrane region of the nicotinic acetylcholine receptor, an important brain and muscle fast signaling protein, was used as a target for docking several channel blockers by means of an automatic docking method. The combination of the independent docking method and molecular models (of the receptor and blockers) reproduced or explained quite accurately experimental data (photoaffinity labeling, site-directed mutagenesis, binding assays). This represents a strong support for the validity of the predictions made for those molecules for which no experimental data is available and also for the models and methods on which are based.

Acetylcholine↗
PubMed1982

Triphenylmethylphosphonium cation distribution as a measure of hormone-induced alterations in white adipocyte membrane potential.

Triphenylmethylphosphonium (TPMP+) partitions into the mitochondrial and cytosolic compartments in the rat white adipocyte in a potential-dependent fashion. The relationship between [3H]TPMP+ distribution, intracellular cAMP generation and lipolysis in response to hormones and cAMP-mimetic compounds was examined. Half-maximal [3H]TPMP+ efflux and glycerol release were produced by 15 and 9 nM adrenocorticotropin, 170 and 110 nM 1-epinephrine, 70 and 27 microM isobutylmethylxanthine and 800 and 750 microM dibutyryl cAMP, respectively. Hormone-stimulated cAMP generation was also correlated with [3H]TPMP+ efflux and lipolysis in terms of concentration dependency. In kinetic experiments, glycerol release and [3H]TPMP+ efflux in response to adrenocorticotropin or cholera toxin proceeded over a similar time course, whereas an earlier rise in cAMP generation was detected. The depolarizing effect of lipolytic compounds was localized to the mitochondrial compartment. When cells were incubated in elevated-[K+]0 buffer, the stimulatory effect of dibutyryl cAMP on [3H]TPMP+ efflux and lipolysis persisted, suggesting that maintenance of the plasma membrane potential is not critical for demonstration of these responses. When the extracellular concentration of serum albumin, which provides binding sites for free fatty acids, was increased from 1 to 3%, an increase in glycerol release and a decrease in [3H]TPMP+ efflux was observed. We suggest that intracellular free fatty acid accumulation in response to lipolytic agents causes dissipation of the mitochondrial membrane potential and efflux of [3H]TPMP+ from the organelle and cell.

Adipose Tissue↗
PubMed1979

Some aspects of the pharmacology of diphenyleneiodonium, a bivalent iodine compound.

1. Previous studies have established that diphenyleneiodonium binds to and inhibits the respiratory enzyme NADH dehydrogenase and also catalyses an exchange of Cl- for OH- across membranes. 2. The hypoglycaemia produced by diphenyleneiodonium was confirmed and shown to be reversible at a dose of 4 mg/kg in starved rats. 3. The lethality of diphenyleneiodonium in mice was cumulative. 4. Presumably as a result of the Cl-/OH- exchange, diphenyleneiodonium-treated rats excreted less Cl- than controls in the first 12 h after administration. However, the swelling of erythrocytes observed in vitro did not occur in vivo. 5. When [125I]diphenyleneiodonium was administered to rats and rabbits, its distribution did not appear to be governed by its binding to NADH dehydrogenase. Reasons for this are discussed. 6 Over 90% of the radioactivity excreted in the faeces of rabbits could not be extracted with boiling water or with dil. HNO3.

Animals↗
PubMed2004

Phosphonium compounds as new and specific inhibitors of bovine serum amine oxidase.

TPP+ (tetraphenylphosphonium ion) and its analogues were found to act as powerful competitive inhibitors of BSAO (bovine serum amine oxidase). The binding of this new class of inhibitors to BSAO was characterized by kinetic measurements. TPP+ can bind to the BSAO active site by hydrophobic and by coulombian interactions. The binding probably occurs in the region of the 'cation-binding site'[Di Paolo, Scarpa, Corazza, Stevanato and Rigo (2002) Biophys. J. 83, 2231-2239]. Under physiological conditions, the association constant of TPP+ for this site is higher than 10(6) M(-1), the change of enthalpy being the main free-energy term controlling binding. Analysis of the relationships between substrate structure and extent of inhibition by TPP+ reveals some new molecular features of the BSAO active site.

Amine Oxidase (Copper-Containing)↗