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191.
Geneste H Backfisch G Braje W Delzer J Haupt A Hutchins CW King LL Lubisch W Steiner G Teschendorf HJ Unger L Wernet W 《Bioorganic & medicinal chemistry letters》2006,16(3):658-662
The synthesis and SAR of novel and selective dopamine D(3)-receptor antagonists based on a 3,4-dihydro-1H-quinolin-2-one, a 1,3,4,5-tetrahydro-benzo[b]azepin-2-one, 1H-quinoline-2,4-dione or a 3,4-dihydro-1H-benzo[b]azepine-2,5-dione scaffold are discussed. A706149 (2.15mg/kg, po) antagonizes PD 128907-induced huddling deficits in rat, a social interaction paradigm. 相似文献
192.
Geneste H Amberg W Backfisch G Beyerbach A Braje WM Delzer J Haupt A Hutchins CW King LL Sauer DR Unger L Wernet W 《Bioorganic & medicinal chemistry letters》2006,16(7):1934-1937
In our efforts to further pursue one of the most selective dopamine D(3)-receptor antagonists reported to date, we now describe the synthesis and SAR of novel and highly selective dopamine D(3) antagonists based on a 1H-pyridin-2-one or on a urea scaffold. The most potent compounds exhibited K(i) values toward the D(3) receptor in the nano- to subnanomolar range and high selectivity versus the related D(2) dopamine receptor. Thus, 1H-pyridin-2-one 7b displays oral bioavailability (F=37%) as well as brain penetration (brain plasma ratio 3.7) in rat. Within the urea series, an excellent D(3) versus D(2) selectivity (>100-fold) could be achieved by removal of one NH group (compound 6), although bioavailability (rat) was suboptimal (F<10%). These data significantly enhance our understanding of the D(3) pharmacophore and are expected to lead to novel approaches for the treatment of schizophrenia. 相似文献
193.
Roussel A Lescar J Vaney MC Wengler G Wengler G Rey FA 《Structure (London, England : 1993)》2006,14(1):75-86
Semliki Forest virus (SFV) is enveloped by a lipid bilayer enclosed within a glycoprotein cage made by glycoproteins E1 and E2. E1 is responsible for inducing membrane fusion, triggered by exposure to the acidic environment of the endosomes. Acidic pH induces E1/E2 dissociation, allowing E1 to interact with the target membrane, and, at the same time, to rearrange into E1 homotrimers that drive the membrane fusion reaction. We previously reported a preliminary Calpha trace of the monomeric E1 glycoprotein ectodomain and its organization on the virus particle. We also reported the 3.3 A structure of the trimeric, fusogenic conformation of E1. Here, we report the crystal structure of monomeric E1 refined to 3 A resolution and describe the amino acids involved in contacts in the virion. These results identify the major determinants for the E1/E2 icosahedral shell formation and open the way to rational mutagenesis approaches to shed light on SFV assembly. 相似文献
194.
Herold MJ Zeitz J Pelzer C Kraus C Peters A Wohlleben G Berberich I 《The Journal of biological chemistry》2006,281(19):13663-13671
Most Bcl-2 family members can localize to intracellular membranes via hydrophobic sequences within their C-terminal portion. We found that the C terminus of the anti-apoptotic family member A1 did not function as a membrane anchor. Instead, this stretch of the protein rendered A1 highly unstable by mediating its polyubiquitination and rapid proteasomal degradation. Moreover, the domain did not only function independently of its position within the A1 protein but when transferred could even destabilize unrelated proteins like enhanced green fluorescent protein and caspase-3. A1 was, however, much more stable in the presence of the Bcl-2 homology-only protein BimEL, suggesting that direct interaction of A1 with pro-apoptotic members of the Bcl-2 family strongly reduces its rate of turnover. We further show that the C-terminal end of A1 also contributes to the anti-apoptotic capacity of the protein. In conclusion, our data demonstrate that the C terminus serves a dual function by controlling the stability of A1 and by amplifying the capacity of the protein to protect cells against apoptosis. 相似文献
195.
Daniela I. Staquicini Rafael M. Martins Silene Macedo Gisela R. S. Sasso Vanessa D. Atayde Maria A. Juliano Nobuko Yoshida 《PLoS neglected tropical diseases》2010,4(3)
Oral infection by Trypanosoma cruzi has been the primary cause of recent outbreaks of acute Chagas'' diseases. This route of infection may involve selective binding of the metacyclic trypomastigote surface molecule gp82 to gastric mucin as a first step towards invasion of the gastric mucosal epithelium and subsequent systemic infection. Here we addressed that question by performing in vitro and in vivo experiments. A recombinant protein containing the complete gp82 sequence (J18), a construct lacking the gp82 central domain (J18*), and 20-mer synthetic peptides based on the gp82 central domain, were used for gastric mucin binding and HeLa cell invasion assays, or for in vivo experiments. Metacyclic trypomastigotes and J18 bound to gastric mucin whereas J18* failed to bind. Parasite or J18 binding to submaxillary mucin was negligible. HeLa cell invasion by metacyclic forms was not affected by gastric mucin but was inhibited in the presence of submaxillary mucin. Of peptides tested for inhibition of J18 binding to gastric mucin, the inhibitory peptide p7 markedly reduced parasite invasion of HeLa cells in the presence of gastric mucin. Peptide p7*, with the same composition as p7 but with a scrambled sequence, had no effect. Mice fed with peptide p7 before oral infection with metacyclic forms developed lower parasitemias than mice fed with peptide p7*. Our results indicate that selective binding of gp82 to gastric mucin may direct T. cruzi metacyclic trypomastigotes to stomach mucosal epithelium in oral infection. 相似文献
196.
197.
Emma Torrecillas Maria del Mar Alguacil Antonio Roldán Gisela Díaz Alicia Montesinos-Navarro Maria Pilar Torres 《Applied and environmental microbiology》2014,80(17):5457-5466
Patterns in plant–soil biota interactions could be influenced by the spatial distribution of species due to soil conditions or by the functional traits of species. Gypsum environments usually constitute a mosaic of heterogeneous soils where gypsum and nongypsum soils are imbricated at a local scale. A case study of the interactions of plants with arbuscular mycorrhizal fungi (AMF) in gypsum environments can be illustrative of patterns in biotic interactions. We hypothesized that (i) soil characteristics might affect the AMF community and (ii) there are differences between the AMF communities (modules) associated with plants exclusive to gypsum soils (gypsophytes) and those associated with plants that show facultative behavior on gypsum and/or marly-limestone soils (gypsovags). We used indicator species and network analyses to test for differences between the AMF communities harbored in gypsophyte and gypsovag plants. We recorded 46 operational taxonomic units (OTUs) belonging to nine genera of Glomeromycota. The indicator species analysis showed two OTUs preferentially associating with gypsum soils and three OTUs preferentially associating with marly-limestone soils. Modularity analysis revealed that soil type can be a major factor shaping AMF communities, and some AMF groups showed a tendency to interact differently with plants that had distinct ecological strategies (gypsophytes and gypsovags). Characterization of ecological networks can be a valuable tool for ascertaining the potential influence of above- and below-ground biotic interactions (plant-AMF) on plant community composition. 相似文献
198.
Belavý DL Bansmann PM Böhme G Frings-Meuthen P Heer M Rittweger J Zange J Felsenberg D 《Journal of applied physiology (Bethesda, Md. : 1985)》2011,111(5):1304-1314
As part of the nutrition-countermeasures (NUC) study in Cologne, Germany in 2010, seven healthy male subjects underwent 21 days of head-down tilt bed rest and returned 153 days later to undergo a second bout of 21-day bed rest. As part of this model, we aimed to examine the recovery of the lumbar intervertebral discs and muscle cross-sectional area (CSA) after bed rest using magnetic resonance imaging and conduct a pilot study on the effects of bed rest in lumbar muscle activation, as measured by signal intensity changes in T(2)-weighted images after a standardized isometric spinal extension loading task. The changes in intervertebral disc volume, anterior and posterior disc height, and intervertebral length seen after bed rest did not return to prebed-rest values 153 days later. While recovery of muscle CSA occurred after bed rest, increases (P ≤ 0.016) in multifidus, psoas, and quadratus lumborum muscle CSA were seen 153 days after bed rest. A trend was seen for greater activation of the erector spinae and multifidus muscles in the standardized loading task after bed rest. Greater reductions of multifidus and psoas CSA muscle and greater increases in multifidus signal intensity with loading were associated with incidence of low back pain in the first 28 days after bed rest (P ≤ 0.044). The current study contributes to our understanding of the recovery of the lumbar spine after 21-day bed rest, and the main finding was that a decrease in spinal extensor muscle CSA recovers within 5 mo after bed rest but that changes in the intervertebral discs persist. 相似文献
199.
200.