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A new multi-gram synthetic route to labeling precursors for the D(2/3) PET agent 18F-fallypride.
Kim K, Miller NR, Sulikowski GA, Lindsley CW
(2008) Bioorg Med Chem Lett 18: 4467-9
MeSH Terms: Benzamides, Chemistry, Pharmaceutical, Chlorine, Dopamine D2 Receptor Antagonists, Drug Design, Mesylates, Models, Chemical, Positron-Emission Tomography, Pyrrolidines, Radiopharmaceuticals, Receptors, Dopamine D2, Receptors, Dopamine D3
Show Abstract · Added March 5, 2014
This Letter describes a new multi-gram synthetic protocol for the preparation of the classic tosylate labeling precursor for the D(2/3) PET agent [(18)F]fallypride. In the course of our studies, we also discovered two novel labeling precusors, the previously undescribed mesylate and chloro congeners of fallypride.
1 Communities
1 Members
0 Resources
12 MeSH Terms
Role of the streptokinase alpha-domain in the interactions of streptokinase with plasminogen and plasmin.
Bean RR, Verhamme IM, Bock PE
(2005) J Biol Chem 280: 7504-10
MeSH Terms: Aminocaproic Acid, Binding Sites, Catalysis, Catalytic Domain, Chlorine, Fibrinolysin, Gene Deletion, Humans, Lipopolysaccharides, Lysine, Microscopy, Fluorescence, Mutation, Plasminogen, Protein Binding, Protein Conformation, Protein Folding, Protein Structure, Tertiary, Recombinant Proteins, Streptokinase, Thermodynamics
Show Abstract · Added January 20, 2015
The role of the streptokinase (SK) alpha-domain in plasminogen (Pg) and plasmin (Pm) interactions was investigated in quantitative binding studies employing active site fluorescein-labeled [Glu]Pg, [Lys]Pg, and [Lys]Pm, and the SK truncation mutants, SK-(55-414), SK-(70-414), and SK-(152-414). Lysine binding site (LBS)-dependent and -independent binding were resolved from the effects of the lysine analog, 6-aminohexanoic acid. The mutants bound indistinguishably, consistent with unfolding of the alpha-domain on deletion of SK-(1-54). The affinity of SK for [Glu]Pg was LBS-independent, and although [Lys]Pg affinity was enhanced 13-fold by LBS interactions, the LBS-independent free energy contributions were indistinguishable. alpha-Domain truncation reduced the affinity of SK for [Glu]Pg 2-7-fold and [Lys]Pg
0 Communities
1 Members
0 Resources
20 MeSH Terms
Pharmacological and autoradiographical characterization of serotonin transporter-like activity in sporocysts of the human blood fluke, Schistosoma mansoni.
Boyle JP, Hillyer JF, Yoshino TP
(2003) J Comp Physiol A Neuroethol Sens Neural Behav Physiol 189: 631-41
MeSH Terms: Animals, Autoradiography, Biological Transport, Active, Chlorine, Dose-Response Relationship, Drug, Fluoxetine, Gene Expression Regulation, Enzymologic, Host-Parasite Interactions, Imipramine, Oocysts, Schistosoma mansoni, Serotonin, Snails, Sodium
Show Abstract · Added February 5, 2016
The present study focuses on the role of the biogenic monoamine serotonin (5-hydroxytryptamine) in the biology of sporocyst stages of the human blood fluke, Schistosoma mansoni, and its importance during obligate development within its snail host Biomphalaria glabrata. Based on previous work demonstrating that snails infected with S. mansoni have reduced levels of 5-hydroxytryptamine, we hypothesized that sporocysts actively transport this molecule from the host milieu. Intact sporocysts isolated in vitro take up exogenous 5-hydroxytryptamine via a high-affinity mechanism (K(m)=1.4 micromol l(-1)), and this serotonin transporter-like activity is dependent upon extracellular Na(+) and Cl(-) and is highly sensitive to previously characterized serotonin transporter inhibitors. Autoradiography suggests that transported [(3)H]5-hydroxytryptamine localizes within the body of the sporocyst, and in many cases is found in apical gland cells. Moreover, serotonin transporter-like activity is absent in free-swimming miracidia, the infective stage for the snail host, and the increase in larval serotonin transporter-like activity after miracidium-to-sporocyst transformation is accompanied by a corresponding decrease in steady-state levels of transcripts for tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis. Overall our data suggest that S. mansoni larvae express surface-exposed serotonin transporter-like molecules, and that the transition from free-living miracidium to parasitic mother sporocyst is characterized by an increased dependence upon exogenous 5-hydroxytryptamine.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Binding and transport in norepinephrine transporters. Real-time, spatially resolved analysis in single cells using a fluorescent substrate.
Schwartz JW, Blakely RD, DeFelice LJ
(2003) J Biol Chem 278: 9768-77
MeSH Terms: Adrenergic Uptake Inhibitors, Adrenergic alpha-Agonists, Anisotropy, Biological Transport, Cell Line, Cells, Cultured, Chlorine, Cocaine, Desipramine, Dopamine Uptake Inhibitors, Dose-Response Relationship, Drug, Fluorescent Dyes, Humans, Image Processing, Computer-Assisted, Kinetics, Microscopy, Fluorescence, Neurons, Norepinephrine, Protein Binding, Protein Structure, Tertiary, Protein Transport, Sodium, Temperature, Time Factors, Transfection, Trypan Blue
Show Abstract · Added July 10, 2013
Monoamine transporters, the molecular targets for drugs of abuse and antidepressants, clear norepinephrine, dopamine, or serotonin from the synaptic cleft. Neurotransmitters, amphetamines, and neurotoxins bind before being transported, whereas cocaine and antidepressants bind to block transport. Although binding is crucial to transport, few assays separate binding from transport, nor do they provide adequate temporal or spatial resolution to describe real-time kinetics or localize sites of active uptake. Here, we report a new method that distinguishes substrate binding from substrate transport using single-cell, space-resolved, real-time fluorescence microscopy. For these studies we use a fluorescent analogue of 1-methyl-4-phenylpyridinium, a neurotoxic metabolite and known substrate of monoamine transporters, to assess binding and transport with 50-ms, sub-micron resolution. We show that ASP(+) (4-(4-(dimethylamino)styrl)-N-methylpyridinium) has micromolar potency for the human norepinephrine transporter, that ASP(+) accumulation is Na(+)-, Cl(-)-, cocaine-, and desipramine-sensitive and temperature-dependent, and that ASP(+) competes with norepinephrine uptake. Using this method we demonstrate that norepinephrine transporters are efficient buffers for substrate, with binding rates exceeding transport rates by 100-fold. Furthermore, substrates bind deep within the transporter, isolated from both the bath and the lipid bilayer. Although transport per se depends on Na(+) and Cl(-), binding is independent of Na(+) and actually increases in low Cl(-). We further demonstrate that ASP(+) interacts with transporters not only in transfected cells but in cultured neurons. ASP(+) is also a substrate for dopamine and serotonin transporters and therefore represents a powerful new technique for studying the biophysical properties of monoamine transporters, an approach also amenable to high throughput assays for drug discovery.
1 Communities
1 Members
0 Resources
26 MeSH Terms
Activation of amino-alpha-carboline, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and a copper phthalocyanine cellulose extract of cigarette smoke condensate by cytochrome P-450 enzymes in rat and human liver microsomes.
Shimada T, Guengerich FP
(1991) Cancer Res 51: 5284-91
MeSH Terms: Aflatoxin B1, Animals, Aroclors, Benzoflavones, Carbolines, Chlorodiphenyl (54% Chlorine), Cytochrome P-450 Enzyme System, DNA, Dose-Response Relationship, Drug, Humans, Imidazoles, In Vitro Techniques, Male, Microsomes, Liver, Mutagens, Plants, Toxic, Quinidine, Rats, Rats, Inbred Strains, SOS Response, Genetics, Safrole, Smoke, Tobacco, beta-Galactosidase
Show Abstract · Added March 5, 2014
The ability of cigarette smoke condensate to induce a genotoxic response has been measured in liver microsomal and reconstituted monooxygenase systems containing rat and human cytochrome P-450 (P-450) enzymes, as determined by umu gene expression in Salmonella typhimurium TA1535/pSK1002. The reactivities of amino-alpha-carboline and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), two compounds known to be present at considerable levels in cigarette smoke condensate, were also determined and compared with regard to genotoxicity. Amino-alpha-carboline and PhIP are activated principally by P-450 1A2 enzymes in human and rat liver microsomes: (a) activation of both compounds was catalyzed efficiently by liver microsomes prepared from rats treated with 5,6-benzoflavone, isosafrole, or the commercial polychlorinated biphenyl mixture Aroclor 1254, and the activities could be considerably inhibited by antibodies raised against P-450 1A1 or 1A2; (b) the rates of activation of these compounds were correlated with the amount of human P-450 1A2 and of phenacetin O-deethylation activity in different human liver microsomal preparations, and these activities were inhibited by anti-P-450 1A2; (c) reconstituted enzyme systems containing P-450 1A enzymes isolated from rats and humans showed the highest rates of activation of amino-alpha-carboline and PhIP. In rat liver microsomes PhIP may also be activated by P-450 3A enzymes; activity was induced in rats treated with pregnenolone 16 alpha-carbonitrile and was inhibited by anti-human P-450 3A4. However, in humans the contribution of P-450 3A enzymes could be excluded as judged by the very low effects of anti-P-450 3A4 on the microsomal activities and poor correlation with P-450 3A4-catalyzed activities in various liver samples. Cigarette smoke condensate strongly inhibited the activation of several potent procarcinogens by human liver microsomes, particularly the reactions catalyzed by P-450 1A2, but was not so inhibitory of the activation reactions catalyzed by P-450 3A4 and of P-450 2D6-catalyzed bufuralol 1'-hydroxylation. Genotoxic components of the cigarette smoke condensate were extracted by using copper phthalocyanine cellulose (blue cotton). Genotoxicity of this extract was observed only after activation by P-450, and the inhibition of P-450 1A2 activities by these extracts was slight.(ABSTRACT TRUNCATED AT 400 WORDS)
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24 MeSH Terms