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| 1 | 基于G-蛋白偶联受体激酶2抑制剂治疗心力衰竭的合理药物设计(英文)显示文摘G protein-coupled receptors(GPCRs)convert extracellular stimuli in the form of hormones,odorants and light into profound changes in cell homeostasis.Their timely desensitization is critical for cells to rapidly respond to changes in their environment and to avoid damage from sustained signaling.Seven GPCR kinases(GRKs)phosphorylate and regulate the activity of most of the^800 GPCRs in the human genome.Although GRKs normally play an adaptive role,in conditions such as chronic heart failure they are overexpressed and linked to disease progression.GRK2 and GRK5 have thus become important targets for the treatment of heart failure and pathological cardiac hypertrophy,respectively.Our lab has determined atomic structures representing all three vertebrate GRK subfamilies,and is now in the midst of a campaign to develop selective inhibitors of these enzymes using structure-based rational design.We have identified the FDA approved drug paroxetine as a selective GRK2 inhibitor,determined the crystal structure of the GRK2·paroxetine complex and,in collaboration with the Koch lab,showed that the drug improves contractility in myocytes and,most impressively,recovery in postmyocardial infarcted mice.Since then,we have identified additional chemical scaffolds that exhibit even higher potency and/or selectivity for GRK5.Using a'hybrid'inhibitor design approach we have generated GRK selective chemical probes that exhibit improved potency and stability and are able to increase inotropy and dampen the hypertrophic response in cardiomyocytes and small animal models.Structural analysis has revealed the molecular basis for selectivity and potency in many of these compounds,allowing for the design of future generations of GRK chemical probes. | John J TESMER Helen V WALDSCHMIDT Marie C CATO Renee BOULEY Osvaldo CRUZ-RODRIGUEZ Scott D LARSEN | 2017 | 中国药理学与毒理学杂志2017，31，10： | 1 |
| 2 | Herpetic stromal keratitis in the reconstituted scid mouse model显示文摘 | Mercadal CM Bouley DM DeStephano D Rouse BT | | 0，，06： | 1 |
| 3 | Determination of 3-demensional zonal renal volumes using contrast-en- hanced computed tomography显示文摘 | Sommer G Bouley D Frisoli J | 2007 | J Comput Assist To- mogr2007，31，2： | 1 |
| 4 | Diet supplemented with yoghurt or milk fermented by Lactobacillus casei DN114001 stimulates growth and brush-border enzyme activities in mouse small intestine 显示文摘 | THOREUX K BALAS D BOULEY C | 1998 | Digestion1998，59，4： | 1 |
| 5 | Leucine-rich repeat-containing,G protein-coupled receptor 48 null mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality显示文摘 | Mazerbourg S Bouley D Sudo S | | 0，，09： | 1 |
| 6 | Study of focused ultrasound tissue damage using MRI and histology 显示文摘 | Chen L Bouley D Yuh E | 1999 | Magn Reson Imaging1999，10，2： | 1 |
| 7 | Progres- sive ataxia, myoelonic epilepsy anti cerebellar apoptosis in cystatin B-deficient mice 显示文摘 | Pennacchio L A Bouley D M Higgins K M | 1998 | Nature Genetics1998，20，3： | 1 |
| 8 | Diagnosis of tu-berculosis in macaques using whole blood in vitro in-terferon-gamma (Primagam) testing显示文摘 | Garcia M A Yee J Bouley D M | 2004 | Comp Med2004，54，： | 1 |
| 9 | New insights into the dynamic regulation of water and acid-base balance by re- nal epithelial calls显示文摘 | BROWN D BOULEY R PAUNESCU TG | 2012 | Am J Physiol2012，302，10： | 1 |
| 10 | A biochemical function for attractin in agouti-induced pigmentation and obesity显示文摘 | Gunn T M Bouley D M Lu X Y Watson S J Schloss man S F Duke-Cohan J S Barsh G S | 2001 | Nat Genet2001，27，： | 1 |
| 11 | Study of focused ultrasound tissue damage using MRI and histology显示文摘 | Chen L Bouley D Yuh E | 1999 | J Magn Reson Imaging1999，10，2： | 1 |
| 12 | Study of focused ultrasound tissue damage using MRI and histology显示文摘 | Chen L Bouley D Yuh E | 1999 | J Magn Resort Imaging1999，10，： | 1 |
| 13 | Detection of early secretory antigenic target-6 antibody for diagnosis of tuberculosis in non-human primates显示文摘 | Kanaujia G V Garcia M A Bouley D M | 2003 | Comparative medicine2003，53，6： | 1 |
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