Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Quinacrine”

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 19 recordsLinked to original sources
PubMed1996

Temperature and ionic strength dependence of quinacrine binding and quinacrine displacement elicited by high concentrations of agonists on the nicotinic acetylcholine receptor.

This paper displays an attempt to elucidate the inhibitory mechanism of the nicotinic acetylcholine receptor (AChR) by spectroscopic means. Specifically, quantitative fluorescence spectroscopy was used to characterize: (1) the mechanism of quinacrine binding to its high-affinity noncompetitive inhibitor site located at the lipid-protein interface of the AChR and (2) the process by which agonists at high concentrations sterically compete for the quinacrine locus. For the first purpose, we study the temperature and ionic strength dependence of quinacrine binding by measuring the apparent dissociation constant (Kd) of quinacrine at the temperature range of 4-23 degrees C and in the sodium chloride (NaCl) concentration order of 0-250 mM. For the second objective, AChR native membranes from Torpedo californica electric organ suspended in buffer 10 mM sodium phosphate, pH 7.4, were preincubated with quinacrine for 2 h in the presence or in the absence of phencyclidine (PCP). Then, the PCP-sensitive quinacrine fluorescence was monitored while high concentrations of cholinergic agonists such as suberyldicholine, acetylcholine (ACh), or carbamylcholine were added to the suspension. By repeating these agonist back titrations at 4, 9, and 15 degrees C in the absence of NaCl and at 4 degrees C in the presence of 100 mM NaCl, we determined the temperature and ionic strength dependence of agonist binding to the quinacrine domain. These experiments suggest that the binding of both quinacrine (measured in the temperature range from 15 to 23 degrees C) and agonists at high concentrations (measured in the temperature regime of 4-15 degrees C) are enthalpy-driven processes, albeit that quinacrine binding is exothermic and agonist binding is endothermic. One plausible model to explain our results is that the quinacrine molecule needs first to be sterically well oriented to further enter into its binding site located in a crevice at the lipid-protein interface, whereas agonist molecules do not. Additionally, a relatively minimal electrostatic component is present in the quinacrine locus. Interestingly, the agonist inhibition constant values determined at 4 degrees C in the presence of 100 mM NaCl showed an exact correlation (slope = 1.03) with the reported concentration values of agonist that inhibit 50% of the maximum 86Rb+ efflux from AChR native vesicles in a 10-s assay with 80-85% of the alpha-bungarotoxin AChR sites occupied at zero membrane potential [S. A. Forman, L. L. Firestone, and K. W. Miller (1987) Biochemistry 26, 2807-2814]. This interdependence strongly supports the existence of a structural relationship between the agonist self-inhibitory binding site and the quinacrine locus. Although there exist evidence indicating that the process of agonist self-inhibition is mediated by a steric blockage of the ion channel, the occurrence of an agonist self-inhibitory binding site not located in the lumen channel indicates an allosteric mechanism for ion channel inhibition.

Animals↗
PubMed1985

Irreversible inhibition of calcium uptake in synaptosomes by quinacrine mustard: relationship to labeling sites of quinacrine mustard.

The sites of interaction of quinacrine with synaptic membranes were labeled with quinacrine mustard. Quinacrine mustard had an inhibitory effect on depolarization-induced calcium uptake by synaptosomes similar to that of quinacrine. The inhibition of depolarization-induced calcium uptake by quinacrine was reduced by 70% after washing, whereas that by quinacrine mustard was not affected. Fluorescence electrophoretograms of the quinacrine mustard-treated synaptic membranes showed that quinacrine mustard specifically labeled two proteins, with corresponding molecular weights of about 37,000 and 32,000.

Animals↗
PubMed2006

Quinacrine but not chloroquine inhibits PMA induced upregulation of matrix metalloproteinases in leukocytes: quinacrine acts at the transcriptional level through a PLA2-independent mechanism.

OBJECTIVE: Macrophages play an important role in rheumatoid arthritis (RA). RA is a disease characterized by the successive accumulation of leukocytes resulting in subsequent destruction of affected joints. Activation of matrix metalloproteinases (MMP) is essential for many physiological as well as many pathological events owing to the essential role of MMP in cell migration. We analyzed the effectiveness of quinacrine as an inhibitor of MMP activation in leukocytes and investigated the mode of action. METHODS: Leukocytes were isolated and treated with quinacrine with or without phorbol myristic acetate (PMA). ELISA and RT-PCR were used to monitor production of MMP-1, MMP-2, MMP-3, and MMP-8 at the mRNA and protein level. RESULTS: Quinacrine suppressed PMA induced MMP-1 release in mononuclear cells (MNC) in a dose- and time-dependent manner. RT-PCR showed that quinacrine downregulated induced as well as noninduced steady-state mRNA levels of MMP-1, MMP-2, and MMP-8, but had no effect on MMP-3. The observed inhibition was not due to effects of quinacrine on phospholipase A2 (PLA2) activity. Adding exogenous arachidonic acid to reconstitute the blocked PLA2 signaling pathways did not result in restoration of PMA induced mRNA transcription. CONCLUSION: Inhibition of MMP by quinacrine might, in part, account for its reported immunosuppressive action. Synthesizing more potent derivatives of quinacrine may be a means of suppressing undesired MMP activation.

Antigens, Human Platelet↗
PubMed1975

Facile preparation of 6-chloro-9-amino-2-hydroxyacridine, a urinary metabolite of quinacrine and quinacrine mustard.

6-Chloro-9-amino-2-hydroxyacridine was found to be a metabolite of both quinacrine and the antimalarial alkylating agent quinacrine mustard. Its structure was confirmed by a one-step reaction of quinacrine with 48 percent hydrobromic acid. The presence of this compound as a metabolite of quinacrine mustard suggests a possible in vivo activation mechanism for its antitumor activity and a pharmacological basis for its toxicity to the liver. In vitro experiments showed that this new compound does react with chromosomes and, therefore, can be both a useful chromosome stain and an intercalating agent.

Acridines↗
PubMed1976

The action of ionizing radiation on DNA in the presence of quinacrine. III. E.S.R. study: spin transfer in gamma-irradiated lyophilized DNA-quinacrine complexes.

E.S.R. spectra of different DNA-quinacrine complexes show as well at 77 K as at 293 K that there exists an electron transfer from the bases to quinacrine facilitated by the overlap of the theta-orbitals of the bases and the intercalated dye. The transfer range may extend over more than 25 or 50 nucleotides depending on the intercalation model considered.

DNA↗
PubMed2006

Quinacrine is mainly metabolized to mono-desethyl quinacrine by CYP3A4/5 and its brain accumulation is limited by P-glycoprotein.

Quinacrine (QA), an antimalarial drug used for over seven decades, has been found to have potent antiprion activity in vitro. To determine whether QA can be used to treat prion diseases, we investigated its metabolism and ability to traverse the blood-brain barrier in mice. In vitro and in vivo, we identified by liquid chromatography-tandem mass spectrometry the major metabolic pathway of QA as N-desethylation and compared our results with an authentic reference compound. The major human cytochrome (P450) isoforms involved in QA mono-desethylation were identified as CYP3A4/5 by using specific chemical and antibody inhibition as well as cDNA-expressed P450 studies. QA transport from the basolateral to apical side in multidrug resistance protein 1 gene (MDR1)-transfected Madin-Darby canine kidney (MDCK) cells was markedly greater than in control MDCK cells and was inhibited by the potent P-glycoprotein (P-gp) inhibitor GG918 (N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-iso-1-quinolynyl)-ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine). In MDR1-knockout (KO) mice, QA brain levels were 6 to 9 times higher after a single i.v. dose of 2 mg/kg QA and 49 times higher after multiple oral doses of 10 mg/kg/day QA for 7 days, compared with those in wild-type (WT) FVB mice. In contrast, the QA levels in plasma, liver, spleen, and kidney were similar after a single 2 mg/kg i.v. dose and <2 times greater after 10 mg/kg oral doses in MDR1-KO mice compared with WT mice. These results indicate that P-gp plays a critical role in transporting QA from the brain.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1993

[Non-surgical female sterilization using quinacrine: efficacy of two insertions of quinacrine pellets].

In a group of 159 women at Santiago du Chili, fertility control by means of chemical occlusion of the utero-tubular junction was assessed. Two transcervical intra-uterine insertions of 216 mg of quinacrine, carried out at an interval of one month and associated with 50 mg of intra-uterine diclofenac and 150 mg of intra-muscular diclofenac resulted in a pregnancy rate after 12 months of 2.1 per 100 women and a Pearl index of 1.63 at 27 months after the sterilization process. The complications and adverse events appear to be similar to those which occur during insertion of an IUD and were minor and transient, disappearing within a few hours or at most 2 days after the procedure.

Adult↗
PubMed1979

Simultaneous staining of sister chromatid exchanges and Q-bands in human chromosomes after treatment with methyl methane sulphonate, quinacrine mustard, and quinacrine.

Human peripheral lymphocyte chromosomes were stained simultaneously for sister chromatid exchanges (SCEs) and Q-banding. No effect of treatment with MMS, QM, and Q on the distribution of SCEs in chromosomes was found compared with controls. The SCEs were distributed between chromosomes roughly according to metaphase length, with the shorter chromosomes underrepresented. The majority of SCEs were located to pale bands, while a few occurred in bright bands and at interfaces between pale and bright bands. A greater frequency than expected of SCEs had occurred at identical sites in homologous chromosomes. This frequency was significantly increased after treatment with MMS.

Chromosome Banding↗
PubMed1977

Energy-linked protonation of quinacrine in beef heart submitochondrial membranes.

1. The absorption spectrum of quinacrine in aqueous solution, in the visible region, changes with the pH of the medium in the pH range from 6.0 to 9.0 with an isosbestic point at 353 nm. This indicates that the monoprotonated (quinacrine - H+) and the diprotonated (quinacrine - 2H+) forms of quinacrine at equilibrium in this pH range have a 1 to 1 stoichiometry. 2. The monoprotonated and the dipronated forms to quinacrine exhibit similar fluorescence emission spectra, but distinctive fluorescence excitation spectra. 3. The relative fluorescence quantum yields of quinacrine in aqueous media of various pH values are estimated. The relative fluorescence quantum yield of quinacrine at pH 9.0 is more than 3 fold of that at pH 6.0. 4. The fluorescence excitation and emission spectra, as well as the relative fluorescence quantum yield of quinacrine associated with non-energized submitochondrial membranes, are similar to those of quinacrine alone. 5. Analyses of the absorption spectra, the fluorescence excitation spectra and the relative fluorescence quantum yield indicate that the energy-linked fluorescence decrease of quinacrine associated with the energized submitochondrial membranes results from the protonation of quinacrine - H+ to form quinacrine - 2H+. 6. Quantitative data are provided indicating that the maximal efficiency of protonation of quinacrine - H+ to form quinacrine - 2H+ depends on the concentration of H+ in the membranes generated through energy coupling, and the concentration of quinacrine - H+ initially present in the reaction medium. Under optimal conditions virtually complete conversion of quinacrine - H+ into quinacrine - 2H+ is observed. 7. The fluorescence intensity of quinacrine, either alone or associated with non-energized submitochondrial membranes, decreases with increasing temperature. When quinacrine is associated with the energized membranes, however, its fluorescence intensity increases slightly with increasing temperature. This unusual fluorescence behavior towards temperature, together with the fact that under optimal conditions virtually all the quinacrine molecules associated with the energized membranes are in the diprotonated form, further substantiate our earlier conclusion that the diprotonated quinacrine molecules are tightly bound to the energized membranes in a fashion which does not permit ready equilibration with the external medium.

Animals↗
PubMed1975

Mechanisms of chromosome banding. V. Quinacrine banding.

A series of biochemical investigations were undertaken to determine the mechanism of Q-banding. The results were as follows: 1. In agreement with previous studies, highly AT-rich DNA, such as poly(dA)-poly(dT), markedly enhanced quinacrine fluorescence while GC containing DNA quenched fluorescence. These effects persisted at DNA concentrations comparable to those in the metaphase chromosome. 2. Studies of quinacrine-DNA complexes in regard to the hypochromism of quanacrine, DNA Tm, DNA viscosity, and equilibrium dialysis, indicated the quinacrine was bound be intercalation with relatively little sid binding. 3. Single or double stranded nucleotide polymers, in the form of complete or partial helices, were 1000-fold more effective in quenching than solutions of single nucleotides, suggesting that base stacking is required for quenching. 4. Studies of polymers in the A conformation, such as transfer RNA and DNA-RNA hybrids, indicated that marked base tilting does not affect the ability of nuclei acids to cause quenching or enhancement of quinacrine fluorescence. 5. Salts inhibit the binding of quinacrine to DNA. 6. Spermine, polylysine and polyarginine, which bind in the small groove of DNA, inhibited quinacrine binding and quenching, while histones, which probably bind in the large groove, had little effect. This correlated with the observation that removal of histones with acid has no effect on Q-banding. 7. Mouse liver chromatin was separated into five fractions. At concentrations of quinacrine from 2 times 10-6 to 2 times 10-5 M all fractions inhibited to varying degrees the ability of the chromatin DNA to bind quinacrine and quench quinacrine fluorescence. At saturating levels of quinacrine two fractions, the 400 g pellet (rich in heterochromatin) and a dispersed euchromatin supernatant fraction, showed a decreased number of binding sites for quinacrine. These two fractions were also the richest in non-histone proteins. 8. DNA isolated from the different fractions all showed identical quenching of quinacrine fluorescenc. 9. Mouse GC-rich, mid-band, AT-rich, and satellite DNA, isolated by CsCL AND Cs-2SO-4-Ag+ centrifugation all showed identical quenching of quinacrine fluorescence, indicating that within a given organism, except for very AT or GC-rich satellites, the variation in base composition is not adequate to explain Q-banding. We interpret these results to indicate that: (a) quinacrine binds to chromatin by intercalation of the three planar rings with the large group at position 9 lying in the small groove of DNA, (b) most pale staining regions are due to a decrease binding of quinacrine, and (c) this inhibition of binding is predominately due to non-histone proteins.

Adenine Nucleotides↗
PubMed1997

The high-affinity quinacrine binding site is located at a non-annular lipid domain of the nicotinic acetylcholine receptor.

This work deals with the localization of the high-affinity non-competitive quinacrine binding site on the muscle-type nicotinic acetylcholine receptor (AChR). Specifically, quantitative steady-state fluorescence spectroscopy is used to determine whether quinacrine binds to a site located at either the annular or the non-annular lipid domain. For this purpose, we measure the ability of spin-labelled phosphatidylcholine (SL-PC) to quench AChR-bound quinacrine, AChR-bound ethidium and membrane-partitioned 7-(9-anthroyloxy)stearate (7-AS) fluorescence. Additionally, we compare the accessibility of SL-PC which is considered to bind only to the annular lipid domain of the AChR with the accessibility of two non-annular domain-sensing lipids such as 5-doxylstearate (5-SAL) and spin-labelled androstane (ASL). Initial experiments using 7-AS established the experimental conditions for maximum SL-PC membrane partitioning. The non-specific quenching elicited by increasing turbidity of the sample after addition of SL-PC is corrected by means of parallel experiments with unlabelled egg yolk phosphatidylcholine. After correction, the SL-PC quenching experiments show the following order in quenching efficiency: 7-AS > quinacrine >> ethidium. The relative intrinsic sensitivity of quinacrine to TEMPO paramagnetic quenching in acetonitrile is considered to be approximately two times higher than that for 7-AS. Thus, SL-PC was found to be more accessible (about 5-fold) to the membrane-partitioned 7-AS than to the quinacrine locus. In addition, SL-PC was virtually not accessible to the high-affinity non-luminal binding site for ethidium. The relative capacity of SL-PC, 5-SAL, and ASL to quench AChR-bound quinacrine fluorescence indicated that the spin-labelled lipid accessibility to the quinacrine binding site follows the order: 5-SAL > ASL >> SL-PC. Examination of the effect of high concentrations of 5-SAL, of its unlabelled parent stearate, and of SL-PC on ethidium and quinacrine binding showed that: (a) both fatty acids displace quinacrine, but not ethidium, from its high-affinity binding site, however (b) 5-SAL was found to be more effective than stearate to displace quinacrine from its locus, whereas (c) SL-PC competes neither for the ethidium locus nor for the quinacrine binding site. The results suggest that the high-affinity binding site for quinacrine is located at a non-annular lipid domain of the AChR. This particular area has been considered to be located at the intramolecular interfaces of the five AChR subunits and/or at the interstices of the transmembrane domains.

Animals↗
PubMed1998

Binding of quinacrine to acidic phospholipids and pancreatic phospholipase A2. Effects on the catalytic activity of the enzyme.

Binding of quinacrine to phospholipids and porcine pancreatic phospholipase A2 (PLA2) was investigated using fluorescence resonance energy transfer, Langmuir films, assay for the enzymatic activity, and molecular modeling. No significant binding of this drug to the zwitterionic phosphatidylcholine was observed whereas a high affinity for acidic phospholipids was revealed by quenching of pyrene-labeled phospholipid analogues. Partial reversal of this binding was observed due to the addition of 4 mM CaCl2. Quinacrine efficiently and independently of the lipid surface pressure penetrated into monolayers of phosphatidylglycerol while only a weak penetration into phosphatidylcholine films was evident. Quinacrine also bound to eosin-labeled PLA2, and the addition of 4 mM CaCl2 reversed this interaction almost completely. In the presence of acidic phospholipids both the drug and the enzyme were attached to the lipid surface. Studies on the influence of quinacrine on the activity of PLA2 toward pyrene-labeled phospholipid analogues revealed that the hydrolysis of phosphatidylcholine was progressively reduced as a function of increasing [quinacrine]. At low [CaCl2] and low quinacrine:lipid molar ratios (<1:5) quinacrine enhanced slightly the rate of hydrolysis of acidic phospholipids whereas at higher drug:lipid molar ratios (>1:2) an inhibition was observed. In the presence of 1 mM CaCl2 quinacrine inhibited PLA2-catalyzed hydrolysis of phosphatidylglycerol only when the drug:lipid molar ratio exceeded 1:1. The presence of 4 mM CaCl2 abolished nearly completely the inhibition with all the substrate analogues used. Our data suggest that the inhibition of PLA2 by quinacrine is due to its binding to the enzyme. This is supported also by molecular modeling which suggested a binding site for quinacrine close to the active site and Ca2+ binding site of the enzyme. Importantly, our data indicate that quinacrine binds avidly to acidic phospholipids and their presence may influence the drug-enzyme interaction and the inhibition of the enzyme action. Accordingly, presence of quinacrine may interfere also with other processes that require the presence of acidic lipids and/or Ca2+, such as the function of the nicotinic acetylcholine receptor.

Animals↗
PubMed1983

Quinacrine mustard inactivates the bovine heart mitochondrial F1-ATPase with the modification of the beta subunit.

The bovine mitochondrial F1-ATPase is reversibly inhibited by quinacrine. The concentration of quinacrine which causes 50% inhibition at pH 7.0 is estimated to be 580 microM. Lineweaver-Burk plots constructed from kinetic data collected at pH 7.0 with equimolar concentrations of Mg2+ and ATP in the reaction mixtures indicate competitive inhibition by quinacrine. Uncompetitive inhibition by quinacrine is indicated by Lineweaver-Burk plots constructed from kinetic data obtained at pH 7.0 with variable ATP concentrations and a constant Mg2+ concentration of 3.0 mM. A KI of 440 microM was calculated from a replot of 1/Vmaxi versus quinacrine concentration using the intercepts of the Lineweaver-Burk plots constructed from the data obtained at a fixed concentration of 3.0 mM Mg2+. Quinacrine mustard is a potent inactivator of the F1-ATPase. The pseudo-first order rate constant, k1, for the inactivation of the enzyme by 500 microM quinacrine mustard is 0.161 min-1 at pH 7.0 and 23 degrees C. Under the same conditions in the presence of 5.0 mM ATP, 5.0 mM ADP, or 5.0 mM Mg2+ plus 5.0 mM ADP, k1 is, respectively: 0.082 min-1, 0.136 min-1, or 0.075 min-1. In the presence of 1.0 mM chlorpromazine or 5.0 mM quinacrine under the above conditions, k1, is 0.089 min-1 and 0.037 min-1, respectively. Free Mg2+ has no effect on the rate of inactivation of the enzyme by quinacrine mustard. The rate of inactivation of the F1-ATPase by quinacrine mustard as a function of pH revealed an apparent pK alpha of 8.0. Examination of the resolved subunits for fluorescence after inactivating the enzyme with quinacrine mustard demonstrated that only the beta subunit was labeled.

Adenosine Triphosphate↗