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排序方式: 共有165条查询结果,搜索用时 9 毫秒
111.
Shankaran Kothandaraman Karla L. Donnely Gabor Butora Richard Jiao Alexander Pasternak Gregori J. Morriello Stephen D. Goble Changyou Zhou Sander G. Mills Malcolm MacCoss Pasquale P. Vicario Julia M. Ayala Julie A. DeMartino Mary Struthers Margaret A. Cascieri Lihu Yang 《Bioorganic & medicinal chemistry letters》2009,19(6):1830-1834
A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity. 相似文献
112.
Reinhart GJ Xie Q Liu XJ Zhu YF Fan J Chen C Struthers RS 《The Journal of biological chemistry》2004,279(33):34115-34122
Efforts to develop orally available gonadotropin-releasing hormone (GnRH) receptor antagonists have led to the discovery of several classes of potent nonpeptide antagonists. Here we investigated molecular interactions of three classes of nonpeptide antagonists with human, rat, and macaque GnRH receptors. Although all are high affinity ligands of the human receptor (K(i) <5 nm), these compounds show reduced affinity for the macaque receptor and bind only weakly (K(i) >1 microm) to the rat receptor. To identify residues responsible for this selectivity, a series of chimeric receptors and mutant receptors was constructed and evaluated for nonpeptide binding. Surprisingly, 4 key residues located in the amino terminus (Met-24) and extracellular loops II (Ser-203, Gln-208) and III (Leu-300) of the GnRH receptor appear to be primarily responsible for species-selective binding. Comparisons of reciprocal mutations suggest that these may not be direct contacts but rather may be involved in organizing extracellular portions of the receptor. These data are novel because most previous reports of residues involved in binding of nonpeptide ligands to peptide-activated G protein-coupled receptors, including the GnRH receptor as well as mono-amine receptors, have identified binding sites in the transmembrane regions. 相似文献
113.
Kohout TA Nicholas SL Perry SJ Reinhart G Junger S Struthers RS 《The Journal of biological chemistry》2004,279(22):23214-23222
Many members of the chemokine receptor family of G protein-coupled receptors utilize multiple endogenous ligands. However, differences between the signaling properties of multiple chemokines through a single receptor have yet to be well characterized. In this study we investigated the early signaling events of CCR7 initiated by its two endogenous ligands, CCL19 and CCL21. Both CCL19 and CCL21 induce G protein activation and calcium mobilization with equal potency. However, only activation by CCL19, not CCL21, promotes robust desensitization of endogenous CCR7 in the human T cell lymphoma cell line H9. Desensitization occurs through the induction of receptor phosphorylation and beta-arrestin recruitment (shown in HEK293 cells expressing CCR7-FLAG). The sites of CCL19-induced phosphorylation were mapped by mutating to alanines the serines and threonines found within kinase phosphorylation consensus sequences in the carboxyl terminus of CCR7. A cluster of sites, including Thr-373-376 and Ser-378 is important for CCL19-mediated phosphorylation of the receptor, whereas residues serine 356, 357, 364, and 365 are important for basal receptor phosphorylation by protein kinase C. Activation of CCR7 by both ligands leads to signaling to the ERK1/2 mitogen-activated protein kinase pathway. However, CCL19 promotes 4-fold more ERK1/2 phosphorylation than does CCL21. The mechanism by which CCL19 activates ERK1/2 was determined to be beta-arrestin-dependent, because it is reduced both by depletion of beta-arrestin-2 with small interfering RNA and by elimination of the phosphorylation sites in the tail of the receptor. Taken together, these findings demonstrate that CCL19 and CCL21 place CCR7 in functionally distinct conformations that are independent of their G protein-coupling potency: one that allows the efficient desensitization of the receptor and activation of ERK1/2, and another that is impaired in these functions. 相似文献
114.
D. Darbar J. Luck N. Davidson T. Pringle G. Main G. McNeill A. D. Struthers 《BMJ (Clinical research ed.)》1996,312(7035):874-879
OBJECTIVE: To determine whether QTc dispersion, which is easily obtained from a standard electrocardiogram, can predict those patients with peripheral vascular disease who will subsequently suffer a cardiac death, despite having no cardiac symptoms or signs. DESIGN: Patients with peripheral vascular disease were followed up for five years after they had had coronary angiography, radionuclide ventriculography, and their QTc dispersion calculated from their 12 lead electrocardiogram. SUBJECTS: 49 such patients were then divided into three groups: survivors (34), cardiac death (12), and non-cardiac death (3). MAIN OUTCOME MEASURE: Survival. RESULTS: The mean (SD; range) ejection fractions were similar in all three groups: survivors 45.9 (11.0; 27.0-52.0), cardiac death 44.0 (7.90; 28.5-59.0), and non-cardiac death 45.3 (4.55; 39.0-50.0). QTc dispersion was significantly prolonged in the cardiac death group compared with in the survivors (86.3(23.9; 41.0-139) v 56.5 (25.4; 25.0-164); P = 0.002). A QTc dispersion > or = 60 ms had a 92% sensitivity and 81% specificity in predicting cardiac death, QTc dispersion in patients with diffuse coronary artery disease was significantly (P < 0.05) greater than in those with no disease or disease affecting one, two, or three vessels. CONCLUSIONS: There is a strong link between QTc dispersion and cardiac death in patients with peripheral vascular disease. QTc dispersion may therefore be a cheap and non-invasive way of assessing the risk of cardiac death in patients with peripheral vascular disease. 相似文献
115.
We sampled populations of forest-floor dwelling cave and ground wētā using footprint tracking tunnels and spotlight transect counts in southern beech forest, New Zealand. Samples were compared to estimates of wētā density based on mark–recapture estimates from 25?m2 enclosures. Both activity indices captured variability in cave wētā in time and space, were strongly correlated with each other, and have the potential for monitoring cave wētā activity levels. Comparisons between indices and cave wētā density estimates were equivocal, as recapture rates were too low to calculate high-resolution density estimates. We also found that cave wētā counts had a curved relationship increasing with temperature, and a negative relationship with increasing shrub and woody debris cover. Based on these preliminary results, tracking tunnels could be a viable method of monitoring cave wētā as they appear more efficient than transect counts and are relatively inexpensive. However, further calibration trials are needed to determine if indices mirror robust population density estimates. 相似文献
116.
Chen M Guo Z Lanier MC Zhao L Betz SF Huang CQ Loweth CJ Ashweek NJ Liu XJ Struthers RS Bradbury MJ Behan JW Wen J O'Brien Z Saunders J Zhu YF 《Bioorganic & medicinal chemistry letters》2007,17(14):3845-3850
A novel series of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives were designed and synthesized as GnRH receptor antagonists. SAR studies led to a series of highly active molecules against both the rat and human receptors. Furthermore, one potent compound, 17j, demonstrated dose-dependent LH suppression in castrated rats. 相似文献
117.
Daniel P. Struthers Lee F.G. Gutowsky Eva C. Enders Karen E. Smokorowski Douglas A. Watkinson Ana T. Silva Maja Cvetkovic Eric Bibeau Steven J. Cooke 《Environmental Biology of Fishes》2017,100(9):1085-1103
Impoundments of free-flowing rivers for hydropower generation often confine fish to relatively small reaches that can restrict movement, limit habitat availability, and alter life history strategies. Here, acoustic telemetry was used to describe the seasonal habitat use, locomotory activity, and depth use for Lake Sturgeon (Acipenser fulvescens) and Walleye (Sander vitreus) within an impounded reach on the Winnipeg River, Manitoba, Canada. Lake Sturgeon foraged and overwintered in the riverine-lacustrine transitionary habitat as well as immediately below the tailrace of the upstream run-of-river facility. Walleye demonstrated high site fidelity to the upstream habitat situated near the tailrace of a hydropower facility. Contrary to Lake Sturgeon, that used multiple habitat types, Walleye used the tailrace for spawning, foraging, and overwintering, given their high residency rates throughout all months at this location. Activity for both species increased with water temperature and when residing in habitat types located farther upstream, but were minimally active during the winter season throughout the impounded reach. On average, Lake Sturgeon utilized 73% of the available depth while Walleye utilized 62% of the available depth across habitat types and months. Overall, the habitat located within the tailrace and below run-of-river facilities should be a conservation priority for both Lake Sturgeon and Walleye populations. There was persistent presence of Lake Sturgeon and Walleye throughout the spawning, foraging, and overwintering periods in the SSGS tailrace and within the first rkm downstream of the tailrace. The habitat proximal to run-of-river facilities generally encompasses small areas of the total potential habitat within impoundments, yet is important to both species studied here. The results provide information on the seasonal habitat use and biological responses to environmental cues for Lake Sturgeon and Walleye that will enhance management and ecological understanding for populations that are confined to impounded reaches. 相似文献
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