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51.
Kaleeckal G. Harikumar Denise Wootten Delia I. Pinon Cassandra Koole Alicja M. Ball Sebastian G. B. Furness Bim Graham Maoqing Dong Arthur Christopoulos Laurence J. Miller Patrick M. Sexton 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(45):18607-18612
The glucagon-like peptide-1 receptor (GLP-1R) is a family B G protein-coupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are peptide based, and there is substantial interest in small molecule modulators for the GLP-1R. Using a variety of resonance energy transfer techniques, we demonstrate that the GLP-1R forms homodimers and that transmembrane helix 4 (TM4) provides the primary dimerization interface. We show that disruption of dimerization using a TM4 peptide, a minigene construct encoding TM4, or by mutation of TM4, eliminates G protein-dependent high-affinity binding to GLP-1(7-36)NH2 but has selective effects on receptor signaling. There was <10-fold decrease in potency in cAMP accumulation or ERK1/2 phosphorylation assays but marked loss of intracellular calcium mobilization by peptide agonists. In contrast, there was near-complete abrogation of the cAMP response to an allosteric agonist, compound 2, but preservation of ERK phosphorylation. Collectively, this indicates that GLP-1R dimerization is important for control of signal bias. Furthermore, we reveal that two small molecule ligands are unaltered in their ability to allosterically modulate signaling from peptide ligands, demonstrating that these modulators act in cis within a single receptor protomer, and this has important implications for small molecule drug design. 相似文献
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van Hooy-Corstjens CS Bulstra SK Knetsch ML Geusens P Kuijer R Koole LH 《Journal of biomedical materials research. Part B, Applied biomaterials》2007,80(2):339-344
Radiopacity in the vast majority of the commercially available acrylic bone cements that are used clinically is provided by particles of either BaSO(4) or ZrO(2). Literature reports have shown these agents to have a detrimental effect on some mechanical properties of the cements as well as on its biological response. We, therefore, have developed a new type of bone cement, for which radiopacity results from the presence of an iodine-containing methacrylic copolymer. The focus of the present work was the comparison of the biocompatibility of this new cement and a commercially available cement that contains barium sulfate. In vitro experiments show that both cements are cytocompatible materials, for which no toxic leachables are found. Implantation of the cements in a rabbit for three months resulted in the occasional presence of a thin fibrous tissue at the cement-bone interface, which is common for acrylic bone cements. Consideration of all the results led to the conclusion that the new cement is as biocompatible as the BaSO(4)-containing one. 相似文献
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Aniket D. Joshi Sandra M. Sanabria‐Bohórquez Guy Bormans Michel Koole Jan De Hoon Anne Van Hecken Marleen Depre Inge De Lepeleire Koen Van Laere Cyrille Sur Terence G. Hamill 《Synapse (New York, N.Y.)》2015,69(1):33-40
Decreased glutamatergic neurotransmission is hypothesized to be involved in the pathophysiology of schizophrenia. Inhibition of glycine transporter Type‐1 (GlyT1) reuptake is expected to increase the glutamatergic neurotransmission and may serve as treatment for cognitive and negative symptoms of schizophrenia. In this article, we present human data from a novel GlyT1 PET tracer, [18F]MK‐6577. In the process of developing a GlyT1 inhibitor therapeutic, a PET tracer can assist in determining the dose with a high probability of sufficiently testing the mechanism of action. This article reports the human PET studies with [18F]MK‐6577 for measuring GlyT1 receptor availability at baseline in normal human subjects and occupancy with a GlyT1 inhibitor, MK‐2637. Studies were also performed to measure radiation burden and the baseline test‐retest (T‐RT) variability of the tracer. The effective dose from sequential whole‐body dosimetry scans in three male subjects was estimated to be 24.5 ± 2.9 µSV/MBq (mean ± SD). The time–activity curves from T‐RT scans modeled satisfactorily using a two tissue compartmental model. The tracer uptake was highest in the pons (VT = 6.7 ± 0.9, BPND = 4.1 ± 0.43) and lowest in the cortex (VT = 2.1 ± 0.5, BPND = 0.60 ± 0.23). VT T‐RT variability measured in three subjects was <12% on average. The occupancy scans performed in a cohort of 15 subjects indicated absence of a reference region. The in vivo potency (Occ50) of MK‐2637 was determined using two methods: A: Lassen plot with a population input function (Occ50 = 106 nM, SE = 20 nM) and B: pseudo reference tissue model using cortex as the pseudo reference region (Occ50 = 141 nM, SE = 21 nM). Synapse 69:33–40, 2015. © 2014 Wiley Periodicals, Inc. 相似文献
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Evaluating the response of tumours to therapy promises to become one of the major applications of in vivo phosphorus (31P) nuclear magnetic resonance spectroscopy. Decreases in the levels of organic phosphates in favour of inorganic phosphate (Pi) as occur in murine tumours after hyperthermia treatment, can be quantified by the ratio ATP/Pi. In this study the relationship between the time of heating (15, 30 and 60 min) and the temperature (43 and 44 degrees C) was investigated in mice with NU-82 tumours by considering the changes in ATP/Pi ratio as a function of both variables. After 30 min treatment at 43 degrees C the percentage decrease in ATP/Pi ratio was similar to that observed after 15 min at 44 degrees C (42 +/- 9 vs. 48 +/- 9); after 60 min at 43 degrees C the decrease was similar to that after 30 min at 44 degrees C (75 +/- 7 vs. 74 +/- 4). These results give further evidence for the validity of a current working definition of thermal dose: thermal dose = t integral of 0 2T-43 dt. In addition this study shows that in vivo 31P NMR spectroscopy can be a useful means for assessment of thermal dose. 相似文献
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