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341.
342.
Kinga Chojnacka Roger L. Papke Nicole A. Horenstein 《Bioorganic & medicinal chemistry letters》2013,23(14):4145-4149
We introduce the term ‘silent agonists’ to describe ligands that can place the α7 nicotinic acetylcholine receptor (nAChR) into a desensitized state with little or no apparent activation of the ion channel, forming a complex that can subsequently generate currents when treated with an allosteric modulator. KC-1 (5′-phenylanabaseine) was synthesized and identified as a new silent agonist for the α7 nAChR; it binds to the receptor but does not activate α7 nAChR channel opening when applied alone, and its agonism is revealed by co-application with the type II positive allosteric modulator PNU-120596 in the Xenopus oocyte system. The concise synthesis was accomplished in three steps with the C–C bonds formed via Pd-catalyzed mono-arylation and organolithium coupling with N-Boc piperidinone. Comparative structural analyses indicate that a positive charge, an H-bond acceptor, and an aryl ring in a proper arrangement are needed to constitute one class of silent agonist for the α7 nAChR. Because silent agonists may act on signaling pathways not involving ion channel opening, this class of α7 nAChR ligands may constitute a new alternative for the development of α7 nAChR therapeutics. 相似文献
343.
In this study we determined the levels of trace elements (zinc, copper, lead, cadmium and mercury) in three layers of bones
of the hip joint (cartilage, compact bone and spongy bone) of 30 red foxes (Vulpes vulpes) from north-western Poland. Concentrations of Cu, Zn, Pb and Cd were determined by atomic absorption spectrophotometry (ICP-AES)
in inductively coupled argon plasma using a Perkin-Elmer Optima 2000 DV. Determination of Hg concentration was performed by
atomic absorption spectroscopy. In cartilage, compact bone and spongy bone samples from the red fox, median concentrations
of the metals studied could be arranged in the following descending series: Zn > Cu > Pb > Cd > Hg, the values ranging from
142 to 0.002 mg/kg dw. There was a significant difference in Cu concentrations, among all the materials analyzed, with much
more Cu found in spongy bone than in compact bone. Significant differences were also noted in the case of Hg concentrations
in cartilage with compact bone and the spongy bone, and between concentrations of this metal in compact bone and spongy bone.
In males, the concentration of Hg in spongy bone was greater than in females. Younger foxes had a higher concentration of
this metal in cartilage than adults. The strongest synergistic relationships were observed in spongy bone between the Zn and
Cu, Zn and Cd, as well as between Cu and Cd. Statistically significant antagonistic relationships were detected between zinc
and lead in compact bone. In addition to monitoring studies conducted on the abiotic environment, an urgent need exists for
long-term monitoring of concentrations of heavy metals with long-term effects on living organisms. An important addition is
provided by biomonitoring studies on domesticated and free-living mammals, including Canidae. 相似文献
344.
345.
Juan F. Marquez Ruiz Kinga Kedziora Mary O’Reilly Jacqueline Maguire Brian Keogh Henry Windle Dermot P. Kelleher John F. Gilmer 《Bioorganic & medicinal chemistry letters》2012,22(24):7573-7577
Budesodine is a synthetic glurocorticoid that undergoes substantial first pass metabolism, limiting systemic exposure. Its use in treatment of inflammatory bowel disease would benefit from a targeting strategy that could lead to a local topical effect, improving safety and increasing anti-inflammatory efficacy. A two-step prodrug strategy involving azoreduction/cyclization that we developed previously for prednisolone is here applied with some variations to budesonide. The budesodine prodrugs were tested using an in vitro azoreductase assay simulating human colonic microflora. The kinetics of amino steroid ester cyclization and its pH dependence was also evaluated. The stability of the prodrugs systems in simulated human duodenal and gastric fluid was evaluated to determine the likelihood of intact intestinal transit. The propionic acid derived prodrug 3 undergoes rapid activation by Clostridium perfingens and its putative reduction product cyclizes with acceptable rapidity when synthesized independently. These properties of 3 suggest that it has potential in management of ulcerative colitis. 相似文献
346.
Colin J. Yates Todd Robinson Grant W. Wardell‐Johnson Gunnar Keppel Stephen D. Hopper Antonius G. T. Schut Margaret Byrne 《Ecology and evolution》2019,9(13):7660-7675
Determining patterns of plant diversity on granite inselbergs is an important task for conservation biogeography due to mounting threats. However, beyond the tropics there are relatively few quantitative studies of floristic diversity, or consideration of these patterns and their environmental, biogeographic, and historical correlates for conservation. We sought to contribute broader understanding of global patterns of species diversity on granite inselbergs and inform biodiversity conservation in the globally significant Southwest Australian Floristic Region (SWAFR). We surveyed floristics from 16 inselbergs (478 plots) across the climate gradient of the SWAFR stratified into three major habitats on each outcrop. We recorded 1,060 species from 92 families. At the plot level, local soil and topographic variables affecting aridity were correlated with species richness in herbaceous (HO) and woody vegetation (WO) of soil‐filled depressions, but not in woody vegetation on deeper soils at the base of outcrops (WOB). At the outcrop level, bioclimatic variables affecting aridity were correlated with species richness in two habitats (WO and WOB) but, contrary to predictions from island biogeography, were not correlated with inselberg area and isolation in any of the three habitats. Species turnover in each of the three habitats was also influenced by aridity, being correlated with bioclimatic variables and with interplot geographic distance, and for HO and WO habitats with local site variables. At the outcrop level, species replacement was the dominant component of species turnover in each of the three habitats, consistent with expectations for long‐term stable landscapes. Our results therefore highlight high species diversity and turnover associated with granite outcrop flora. Hence, effective conservation strategies will need to focus on protecting multiple inselbergs across the entire climate gradient of the region. 相似文献