共查询到20条相似文献,搜索用时 15 毫秒
1.
2-Fluoronorepinephrine (IC50 ≈0.7 μM) is a relatively selective ligand for displacement of radioactive dihydroalprenolol from β1-adrenergic receptors in membrane preparations from rat cerebral cortex. It is less potent (IC50 ≈10 μM) in displacing dihydroalprenolol from β2-adrenergic receptors in rat cerebellar membranes and in displacing clonidine from α2-adrenergic receptors in rat cerebral cortical membranes. It is much less potent (IC50 > 100 μM) in displacing WB-4101 from α1-adrenergic receptors in rat cerebral cortical membranes. In contrast, 6-fluoronorepinephrine is relatively selective for α-adrenergic receptors, being at least 50–200 times more potent at such receptors than at β-adrenergic receptors. 5-Fluoronorepinephrine like norepinephrine does not exhibit remarkable selectivity towards α- and β-adrenergic receptors. The 2-, 5- and 6-fluorodopamines are more potent ligands at α1-adrenergic receptors than at α2- and β-adrenergic receptors but the specificity is not markedly affected by the position of the fluorine substituent. The results suggest that the specificity exhibited by the 2- and 6-fluoronorepinephrine at adrenergic receptors is not primarily due to fluorine-induced changes in the physicochemical properties of the aromatic ring, but instead to stereoselective interactions of the ethanolamine side chain of norepinephrine with fluorine at either the 2- or 6-ring positron. The fluorodopamines like dopamine itself are more potent at dopaminergic than at α- or β-adrenergic receptors. The 2-, 5- and 6-fluorodopamines are all nearly equipotent with dopamine in the displacement of radioactive spiroperidol from dopaminergic receptors in membrane preparations from rat striatum, while the 2- and 6-fluorodopamine are somewhat less potent than dopamine or 5-fluorodopamine in displacement of radioactive apomorphine in striatal membranes. 相似文献
2.
《Journal of receptor and signal transduction research》2013,33(1-4):677-690
AbstractDesensitization of G-protein coupled receptors following agonist occupancy is accompanied by two temporally distinguishable cellular trafficking phenomena of the receptors referred to as sequestration and down regulation. For the β2-adrenergic receptor, sequestration occurs within minutes of agonist binding and results in a reversible internalization and loss of cell surface receptor binding. With longer occupancy, greater than 1 hour, down regulation results in a variable loss of the complement of cellular receptors. Here we compare the two methods that have been used to monitor these receptor changes, competition of whole cell hydrophobic ligand binding (125I-pindolol) with a hydrophilic ligand (CGP-12177) and now cytometry quantification of immunologically tagged β2-adrenergic receptor. While both methods give reliable results, we show that because of a 1:500 partitioning of the hydrophilic ligand into cells, slightly different conditions should be used to assess basally or agonist stimulated sequestered receptor levels. Using a sequestration defective β2-adrenergic receptor mutant we demonstrate that even though sequestration and down regulation behave as independent processes, sequestration can significantly affect the rate at which receptors are lost by the down regulatory process by removing receptors from the pool of down regulating receptors. A mathematical model expressing these relationships is provided. 相似文献
3.
The process of evaluating the in vivo efficacy of non–peptidyl receptor antagonists in animal models is frequently complicated by failure of compounds displaying high affinity against the human receptors to show measurable affinity at the corresponding rodent receptors. In order to generate a suitable animal model in which to evaluate the in vivo activity of non–peptidyl glucagon receptor antagonists, we have utilized a direct targeting approach to replace the murine glucagon receptor with the human glucagon receptor gene by homologous recombination. Specific expression of the human glucagon receptor (GR) in the livers of transgenic mice was confirmed with an RNase protection assay, and the pharmacology of the human GRs expressed in the livers of these mice parallels that of human GR in a recombinant CHO cell line with respect to both binding of 125I–glucagon and the ability of glucagon to stimulate cAMP production. L–168,049, a non–peptidyl GR antagonist selective for the human GR shows a 3.5 fold higher affinity for liver membrane preparations of human GR expressing mice (IC50=172±98nM) in the presence of MgCl2 in marked contrast to the measured affinity of the murine receptor (IC50=611±97nM) for this non–peptidyl antagonist. The human receptors expressed are functional as measured by the ability of glucagon to stimulate cAMP production and the selectivity of this antagonist for the human receptor is further verified by its ability to block glucagon–stimulated cyclase activity with 5 fold higher potency (IC50=97.2±13.9nM) than for the murine receptor (IC50=504±247nM). Thus we have developed a novel animal model for evaluating GR antagonists in vivo. These mice offer the advantage that the regulatory sequences which direct tissue specific and temporal expression of the GR have been unaltered and thus expression of the human gene in these mice remains in the normal chromosomal context. 相似文献
4.
Claire M. Fraser Roger Greguski Barbara Eddy J. Craig Venter 《Journal of cellular biochemistry》1983,21(3):219-231
The combination of immunological advances with membrane receptor research has promoted rapid progress in the molecular characterization of neurotransmitter receptor molecules. We have to date produced monoclonal antibodies to β1-, β2-, and β1-adrenergic, D2-dopaminergic, and muscarinic receptors. In addition we have discovered that some allergic respiratory disease patients possess circulating autoantibodies to β2-adrenergic receptors. These antireceptor antibodies in conjunction with specific receptor affinity reagents have allowed us to isolate, purify, and begin to characterize α- and β-adrenergic, dopaminergic, and muscarinic receptors. For example, immunoprecipitation of turkey erythrocyte β1 receptors with monoclonal antibodies yields a single polypeptide Mr 65–70 K. In contrast, purification of β2-adrenergic receptors using either autoantibodies or monoclonal antibodies yields a receptor species with a subunit of Mr 55–59 K. Autoantibodies to β2 receptors demonstrate a 50–100% homology among β2 receptors from humans to rats, whereas monoclonal antibody FV-104 recognizes a determinant in the ligand binding site of all β1 and β2 receptors tested to date. These data suggest that β1- and β2-adrenergic receptors may have evolved from a common ancestor, perhaps by gene duplication. 相似文献
5.
Jian Liu Yu Wen Lina Gao Liang Gao Fengjun He Jingxian Zhou 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):72-84
Abstract Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragment-based virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC50 = 15.0?nM) and modest anti-proliferative activity (IC50 = 785.8?nM). Through two rounds of optimisation, the indazole derivative 9?u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC50 = 3.3?nM) and cellular activity (IC50 = 468.2?nM). Moreover, 9?u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1. 相似文献
6.
Eija Martikkala Minna Lilja Jenni Lunden Pekka Hänninen Harri Härmä 《Analytical biochemistry》2009,392(2):103-6887
High-sensitivity, high-throughput, and user-friendly lanthanide-based assays for receptor-ligand interactions provide an attractive alternative to the traditional radioligand displacement assays. In this study, three small-molecule pindolol ligand derivatives were synthesized and their binding properties were tested in a radioligand displacement assay. The ligand derivatives were further labeled with fluorescent europium(III) chelate for β2-adrenergic receptor-ligand binding assay. The europium-labeled pindolol ligands having no spacer (C0) or a 12-carbon spacer (C12) arm bound to the human β2-adrenergic receptors overexpressed in human embryonic kidney HEK293i cells. Europium ligand with a 6-carbon spacer arm (C6) showed no binding. Competitive binding assays were developed with the functional labeled ligands. The IC50 values for β2-adrenergic antagonist propranolol were 60 and 37 nM, the Z′ values were 0.51 and 0.77, and the signal-to-background ratios were 5.5 and 16.0 for C0 and C12, respectively. This study shows that functional time-resolved fluorescent assays can be constructed using fluorescent lanthanide chelates conjugated to small-molecule ligands. 相似文献
7.
《Bioorganic & medicinal chemistry》2016,24(21):5602-5610
Progesterone is involved in multiple physiological processes, including female reproduction, via binding to the progesterone receptor (PR). We have developed 6-arylcoumarins such as 5 and 6 as non-steroidal PR antagonists with receptor-binding-dependent fluorescence. In this study, we investigated the structure–activity relationships and fluorescence properties of coumarin derivatives bearing a heterocyclic aromatic moiety. Among these derivatives, 7c (IC50: 34 nM) and 10b (IC50: 24 nM) showed more potent PR-antagonistic activity than lead compounds 5 (IC50: 500 nM) and 6 (IC50: 65 nM) in alkaline phosphatase (AP) assay. Compound 9b showed solvent-dependent fluorescence intensity, exhibiting strong fluorescence in the presence of PR LBD only in buffer solution. On the other hand, 10b showed a solvent-dependent shift of the fluorescence maximum wavelength in the presence of PR LBD. These results indicate that 6-arylcoumarin will be a useful scaffold for PR antagonists and fluorescent probes targeting PR. 相似文献
8.
James I. Fells Ryoko Tsukahara Jianxiong Liu Gabor Tigyi Abby L. Parrill 《Bioorganic & medicinal chemistry》2009,17(21):7457-7464
Compound 5 ([5-(3-nitrophenoxy)-1,3-dioxo-1,3-dihydro-2-isoindol-2-yl]acetic acid) was identified as a weak selective LPA3 antagonist (IC50 = 4504 nM) in a virtual screening effort to optimize a dual LPA2 and 3 antagonist. Structure-based drug design techniques were used to prioritize similarity search matches of compound 5. This strategy rapidly identified 10 novel antagonists. The two most efficacious compounds identified inhibit activation of the LPA3 receptor by 200 nM LPA with IC50 values of 752 nM and 2992 nM. These compounds additionally define changes to our previously reported pharmacophore that will improve its ability to identify more potent and selective LPA3 receptor antagonists. The results of the combined computational and experimental screening are reported. 相似文献
9.
《Journal of receptor and signal transduction research》2013,33(5):281-296
AbstractRat C6 glioma cells have both β1- and β2-adrenergic receptors in ~ 7:3 ratio. When the cells were exposed to the β-adrenergic agonist isoproterenol, there was a rapid sequestration of up to 50% of the surface receptor population over a 30-min period as measured by the loss of binding of the hydrophilic ligand [3H] CGP-12177 to intact cells. Using the β2-selective antagonist CGP 20712A to quantify the proportion of the two subtypes, it was found that although both β1 and β2 receptors were sequestered, the latter were sequestered initially twice as fast as the former. More prolonged agonist exposure led to a down-regulation of ~ 90% of the total receptor population by 6 h as measured by the loss of binding of the more hydrophobic ligand [125I] iodocyanopindolol to cell lysates. The two subtypes, however, underwent down-regulation with similar kinetics. Treatment of the cells with agents that raise cyclic AMP levels such as cholera toxin and forskolin resulted in a slower, but still coordinated down-regulation of both subtypes. Thus, there appears to be both independent and coordinate regulation of endogenous β1-and β2-adrenergic receptors in the same cell line. 相似文献
10.
《Bioorganic & medicinal chemistry》2019,27(23):115144
Colchicine is the major alkaloid isolated from the plant Colchicum autumnale, which shows strong therapeutic effects towards different types of cancer. However, due to the toxicity of colchicine towards normal cells its application is limited. To address this issue we synthesized a series of seven triple-modified 4-bromothiocolchicine analogues with amide moieties. These novel derivatives were active in the nanomolar range against several different cancer cell lines and primary acute lymphoblastic leukemia cells, specifically compounds: 5–9 against primary ALL-5 (IC50 = 5.3–14 nM), 5, 7–9 against A549 (IC50 = 10 nM), 5, 7–9 against MCF-7 (IC50 = 11 nM), 5–9 against LoVo (IC50 = 7–12 nM), and 5, 7–9 against LoVo/DX (IC50 = 48–87 nM). These IC50 values were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies revealed that colchicine and selected analogues induced characteristics of apoptotic cell death but manifested their effects in different phases of the cell cycle in MCF-7 versus ALL-5 cells. Specifically, while colchicine and the studied derivatives arrested MCF-7 cells in mitosis, very little mitotically arrested ALL-5 cells were observed, suggesting effects were manifest instead in interphase. We also developed an in silico model of the mode of binding of these compounds to their primary target, β-tubulin. We conducted a correlation analysis (linear regression) between the calculated binding energies of colchicine derivatives and their anti-proliferative activity, and determined that the obtained correlation coefficients strongly depend on the type of cells used. 相似文献
11.
《Journal of receptor and signal transduction research》2013,33(1-4):263-281
AbstractWe have examined the mechanism of homologous regulation of MSH receptor binding and receptor-mediated adenylate cyclase activation in three human and two mouse melanoma cell lines. Pretreatment with α-MSH resulted in a time- and dose-dependent up-regulation of MSH receptors in human D10 and 205 melanoma cells whereas in human HBL and in mouse B16–F1 and Cloudman S91 cells α-MSH induced receptor down-regulation. Up-regulation of receptors was maximal after a 24–h incubation period and an α-MSH concentration of 100 nM (EC50 = 2.4 nM). The increase in α-MSH binding was independent of adenylate cyclase activation and protein synthesis and appeared to be caused by recruitment of spare receptors. The structural requirements of the peptide for triggering this process differed from those found in receptor-binding analyses. Receptor down-regulation was maximal after 12 h and hence more rapid than up-regulation. In B16–F1 cells, 10 nM α-MSH caused the disappearance of 85–90% of the MSH receptors, the EC50 of 0.23 nM lying exactly between that for α-MSH-induced melanogenesis (0.027 nM) and the dissociation constant of receptor binding (1.31 nM). Down-regulation in B16–F1 cells appears to be the consequence of receptor internalization following MSH binding and seems to be initiated during an early step in MSH signalling, preceding the activation of adenylate cyclase and the cAMP signal. Receptor up- and down- regulation were not accompanied by an alteration in affinity to a-MSH, as demonstrated by Scatchard analysis of the binding curves. 相似文献
12.
II. Beta-adrenergic receptors and catecholamine sensitive adenylate cyclase in the developing rat lung 总被引:1,自引:0,他引:1
β-Adrenergic receptors were identified in membrane fractions of fetal and postnatal rat lung with the β-adrenergic antagonist (?)?[3H] dihydroalprenolol, (?)?[3H] DHA. β-Receptor number (Bmax) increased 11-fold from day 18 of gestation to day 28 of postnatal life, 46±7 to 491±69 femtomole·mg?1 protein. Neither the KD, approximately 0.8nM for [3H]DHA, nor the β-adrenergic subtype changed with age. Classical agonists competed for the β-receptor with properties characteristic of β2-adrenergic binding. Analysis of the inhibition of receptor binding by selective β-adrenergic agents demonstrated approximately 75% β2 and 25% β1 β-adrenergic subtypes in fetal rat lung membranes. The increase in β-adrenergic receptor during development was associated with adenylate cyclase activity which was sensitive to catecholamines at all ages studied, supporting the possible role of the β-adrenergic receptor system in the postnatal regulation of pulmonary function. 相似文献
13.
《Journal of receptor and signal transduction research》2013,33(1-4):257-281
AbstractMammalian β-adrenergic receptors are glycoproteins consisting of a single polypeptide chain of Mr ~64,000. Treatment of purified [125I]-labeled hamster lung β-adrenergic receptor with α-mannosi-dase reveals two discrete populations of receptor consistent with previous studies using membrane bound photoaffinity-labeled receptor. Treatment of the [125I]-labeled receptor with endo-glycosidase F results initially in the formation of a Mr ~57,000 peptide which is further converted to Mr ~49,000 suggesting that there are two N-linked carbohydrate chains per receptor polypeptide. Exoglycosidase treatments and lectin chromatography of the [125I]-labeled receptor reveals the presence of two complex type carbohydrate chains (~10% of which are fucosylated) on ~45% of the receptors. The remaining ~55% of the receptors appear to contain a mixture of carbohydrate chains (possibly high mannose, hybrid and complex type chains). Deglycosylation of the receptor by endoglycosidase F does not appear to alter the binding affinity of the receptor for a variety of β-adrenergic agonists and antagonists. Moreover, the ability of control, α-mannosidase sensitive or insensitive (fractionated on immobilized wheat germ agglutinin) and neuraminidase, α-mannosidase or endoglycosidase F treated receptors to interact with the stimulatory guanine nucleo-tide regulatory protein in a reconstituted system were virtually identical. The deglycosylated receptor was also unaltered in its heat lability as well as its susceptibility to a variety of proteases. These findings demonstrate that the carbohydrate portion of the β-receptor does not contribute to determining either its specificity of ligand binding or coupling to the adenylate cyclase system. 相似文献
14.
Background
Mammalian receptors that couple to effectors via heterotrimeric G proteins (e.g., beta 2-adrenergic receptors) and receptors with intrinsic tyrosine kinase activity (e.g., insulin and IGF-I receptors) constitute the proximal points of two dominant cell signaling pathways. Receptors coupled to G proteins can be substrates for tyrosine kinases, integrating signals from both pathways. Yeast cells, in contrast, display G protein-coupled receptors (e.g., alpha-factor pheromone receptor Ste2) that have evolved in the absence of receptor tyrosine kinases, such as those found in higher organisms. We sought to understand the motifs in G protein-coupled receptors that act as substrates for receptor tyrosine kinases and the functional consequence of such phosphorylation on receptor biology. We expressed in human HEK 293 cells yeast wild-type Ste2 as well as a Ste2 chimera engineered with cytoplasmic domains of the beta2-adrenergic receptor and tested receptor sequestration in response to activation of the insulin receptor tyrosine kinase.Results
The yeast Ste2 was successfully expressed in HEK 293 cells. In response to alpha-factor, Ste2 signals to the mitogen-activated protein kinase pathway and internalizes. Wash out of agonist and addition of antagonist does not lead to Ste2 recycling to the cell membrane. Internalized Ste2 is not significantly degraded. Beta2-adrenergic receptors display internalization in response to agonist (isoproterenol), but rapidly recycle to the cell membrane following wash out of agonist and addition of antagonist. Beta2-adrenergic receptors display internalization in response to activation of insulin receptors (i.e., cross-regulation), whereas Ste2 does not. Substitution of the cytoplasmic domains of the β2-adrenergic receptor for those of Ste2 creates a Ste2/beta2-adrenergic receptor chimera displaying insulin-stimulated internalization.Conclusion
Chimera composed of yeast Ste2 into which domains of mammalian G protein-coupled receptors have been substituted, when expressed in animal cells, provide a unique tool for study of the regulation of G protein-coupled receptor trafficking by mammalian receptor tyrosine kinases and adaptor proteins. 相似文献15.
(?) [3H]Dihydroalprenolol, a potent competitive β-adrenergic antagonist can be used to directly study β-adrenergic receptors by ligand binding techniques in an intact cell system, the frog erythrocyte. At 37°, binding reached equilibrium within 1 minute. Upon addition of excess unlabeled propranolol, complete dissociation of receptor bound ligand occurred within 1 minute. The characteristics of (?) [3Hdihydroalprenolol binding to β-adrenergic receptors in intact cells were quite similar to those previously demonstrated with isolated membrane fractions. The equilibrium dissociation constant for (?) [3H]dihydroalprenolol was 1.5 nM. Order of potency of agonists and antagonists in competing for the binding sites was appropriate for the β-adrenergic receptor as was the stereospecificity of binding ((?) isomers more potent than (+) isomers). Saturation studies with these intact cells indicated 1700 binding sites/cell in excellent agreement with the number previously estimated from membrane studies. Preincubation of cells with 10?5M isoproterenol produced a 36% fall in number of β-adrenergic receptors. It is concluded that (?) [3H]dihydroalprenolol can be used to directly study the properties and regulation of β-adrenergic receptors in intact cell as well as broken cell preparations. 相似文献
16.
Rie Nishikawa-Shimono Yoshinori Sekiguchi Takeshi Koami Madoka Kawamura Daisuke Wakasugi Kazuhito Watanabe Shunichi Wakahara Kayo Kimura Susumu Yamanobe Tetsuo Takayama 《Bioorganic & medicinal chemistry》2013,21(24):7674-7685
In this study, we describe the synthesis and structure–activity relationship (SAR) of a series of isoquinoline chemoattractant receptor–homologous molecule expressed on Th2 cells (CRTH2) antagonists. TASP0376377 (15-20), one of the most potent compounds, showed a potent binding affinity (IC50 = 19 nM) in addition to the excellent functional antagonist activity (IC50 = 13 nM). Moreover, the efficacy of this compound in a chemotaxis assay (IC50 = 23 nM) was in good agreement with its potency as a CRTH2 antagonist. In addition, 15-20 exhibited greater selectivity in binding to CRTH2 than to the DP1 prostanoid receptor (IC50 >1 μM) or the enzymes COX-1 and COX-2 (IC50 >10 μM). 相似文献
17.
Takuto Kojima Michiyo Mochizuki Takafumi Takai Yasutaka Hoashi Sachie Morimoto Masaki Seto Minoru Nakamura Katsumi Kobayashi Yuu Sako Maiko Tanaka Naoyuki Kanzaki Yohei Kosugi Takahiko Yano Kazuyoshi Aso 《Bioorganic & medicinal chemistry》2018,26(9):2229-2250
A new class of corticotropin releasing factor 1 (CRF1) receptor antagonists characterized by a tricyclic core ring was designed and synthesized. Novel tricyclic derivatives 2a–e were designed as CRF1 receptor antagonists based on conformation analysis of our original 2-anilinobenzimidazole CRF1 receptor antagonist. The synthesized tricyclic derivatives 2a–e showed CRF1 receptor binding activity with IC50 values of less than 400?nM, and the 1,2,3,4-tetrahydropyrimido-[1,2-a]benzimidazole derivative 2e was selected as a lead compound with potent in vitro CRF1 receptor binding activity (IC50?=?7.1?nM). To optimize the pharmacokinetic profiles of lead compound 2e, we explored suitable substituents on the 1-position and 6-position, leading to the identification of compound 42c-R, which exhibited potent CRF1 receptor binding activity (IC50?=?58?nM) with good oral bioavailability (F?=?68% in rats). Compound 42c-R exhibited dose-dependent inhibition of [125I]-CRF binding in the frontal cortex (5 and 10?mg/kg, p.o.) as well as suppression of locomotor activation induced by intracerebroventricular administration of CRF in rats (10?mg/kg, p.o.). These results suggest that compound 42c-R successfully binds CRF1 receptors in the brain and exhibits the potential to be further examined for clinical studies. 相似文献
18.
《Journal of receptor and signal transduction research》2013,33(1-4):7-21
AbstractThe adenylate cyclase-stimulatory β2-adrenergic receptor has been purified to apparent homogeneity from hamster lung. Partial amino acid sequence obtained from isolated CNBr peptides was used to clone the gene and cDNA for this receptor. The predicted amino acid sequence for the hamster β2-adrenergic receptor revealed that the protein consists of a single polypeptide chain of 418 aa with consensus N-glycosylation and phosphorylation sites predicted by previous in vitro data. The most striking feature of the receptor protein however, is that it contains seven stretches of hydrophobic residues similar to the proposed seven transmembrane segments of the light receptor rhodopsin. Significant amino acid homology (30-35%) can be found between the hamster β2-adrenergic receptor and rhodopsin within these putative membrane spanning regions. Using a hamster β2-adrenergic receptor probe, the gene and cDNA for the human β2-adrenergic receptor were isolated, revealing a high degree of homology (87%) between the two proteins from different species. Unlike the genes encoding the family of opsin pigments, of which rhodopsin is a member, the genes encoding both hamster and human β2-adrenergic receptors are devoid of introns in their coding as well as 5′ and 3′ untranslated nucleotide sequences. The cloning of the genes and the elucidation of the aa sequences for these G-protein coupled receptors should help to determine the structure-function as well as the evolutionary relationship of these proteins. 相似文献
19.
Mohammed I. El-Gamal 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):1160-1166
A series of eighteen pyrrolo[3,2-c]pyridine derivatives were tested for inhibitory effect against FMS kinase. Compounds 1e and 1r were the most potent among all the other tested analogues (IC50?=?60?nM and 30?nM, respectively). They were 1.6 and 3.2 times, respectively, more potent than our lead compound, KIST101029 (IC50?=?96?nM). Compound 1r was tested over a panel of 40 kinases including FMS, and exerted selectivity against FMS kinase. It was further tested against bone marrow-derived macrophages (BMDM) and its IC50 was 84?nM (2.32-fold more potent than KIST101029 (IC50?=?195?nM)). Compound 1r was also tested for antiproliferative activity against a panel of six ovarian, two prostate, and five breast cancer cell lines, and its IC50 values ranged from 0.15–1.78?µM. It possesses also the merit of selectivity towards cancer cells than normal fibroblasts. 相似文献
20.
《Journal of receptor and signal transduction research》2013,33(3):267-283
AbstractIn rat liver membranes three types of ligand binding were seen using [3H]-dihydroalprenolol (DHA) and [125I]-hydroxybenzylpindolol (HYP): binding stereospecifically displaced by β-adrenergic agonists and antagonists, binding nonstereospecifically displaced by β-adrenergic antagonists, and binding which was not displaced by β-adrenergic agonists or antagonists.The magnitude of the nonstereospecific displaceable binding varied with the physiological state of the animal. It was sufficient to prevent the quantitation of the stereospecific displaceable binding in some preparations from young rats but in all preparations of rats greater than 150 g or more than about 6 weeks of age. In adrenalectomized weanling rats 10–30% of the total binding was of nonstereospecific displaceable type while in control rats it comprised up to 60% of the total binding. Addition of 5 X 10-6 M phentolamine to the assay eliminated a large proportion of the nonstereospecific displaceable binding. When phentolamine was included in the assay, liver membranes from weanling rats stereo-specifically bound 30–35% of total binding; membranes from adrenalectomized rats showed stereospecific binding of up to 50 to 80%.Because the amount of displaceable, nonstereospecific binding varied greatly depending on the physiologic state of the animals, stereospecific displacement should be monitored for every type of liver membrane preparation. Furthermore, animal age is an important variable. Using the published antagonist binding methodology (DHA or HYP) in liver membranes, it is not presently possible to quantitate liver β-adrenergic receptors in normal rats that have reached maturity. 相似文献