Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A functionalized congener approach was used to design ligands for muscarinic cholinergic receptors (mAChRs). A series of omega-functionalized alkyl amides of N-methyl-4-(1-pyrrolidinyl)-2-butynamine (22) were prepared as functionalized analogues of UH 5 [N-methyl-N-[4-(1-pyrrolidinyl)-2-butynyl]acetamide], a muscarinic agonist related to oxotremorine. Intermediate 22 was coupled to a series of Boc-protected omega-amino acids, and the resulting amides were deprotected and acylated. Intermediate 22 was also acylated with succinic anhydride and derivatized. The synthetic intermediates and final compounds were evaluated in vitro for their effects on the turnover of phosphatidylinositides in SK-N-SH human neuroblastoma cells that express m3AChRs, and on the production of cyclic AMP in NG108-15 neuroblastoma x glioma cells that express only m4AChRs. The displacement of [3H]-N-methylscopolamine was also measured in membrane preparations from each of these cell lines. Conjugates of glycine and beta-alanine were agonists at m4AChRs, having little or no activity at m3AChRs. The potency in displacement of [3H]-N-methylscopolamine from both m3- and m4AChRs generally increased with increasing chain lengths of the omega-aminoalkyl congeners. The amides of 7-aminoheptanoic acid and 8-aminooctanoic acid, and their Boc-protected derivatives, had comparable affinities to UH 5 (Ki = 5.0 and 4.5 microM at m3AChRs and at m4AChRs, respectively) at both receptors but lacked any agonist effects.
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PMID:Functionalized congener approach for the design of novel muscarinic agents. Synthesis and pharmacological evaluation of N-methyl-N-[4-(1-pyrrolidinyl)-2-butynyl] amides. 215 27

A C6 glioma cell line stably transfected with the human kappa opioid receptor (kappaOR) was used to characterize receptor binding and G protein activation via the kappaOR by a comprehensive series of opioid ligands. The ligand-binding affinity for [3H]5alpha,7alpha, 8beta(-)-N-methyl-N-(7-Cl-pyrrolidinyl)-1-oxaspiro(4, 5)dec-8-yl)benzene acetamide (U69593) was similar to that observed in monkey brain membranes and was 10-fold lower in the presence of sodium and GDP. Both peptide and nonpeptide agonists maximally stimulated [35S]GTPgammaS binding. The stimulation of [35S]GTPgammaS binding was blocked by pretreatment of cells with pertussis toxin. Partial stimulation of [35S]GTPgammaS binding via the kappaOR was observed for several ligands that are antagonists at the mu opioid receptor, suggesting an additional mechanism of drug action. The ability of isomers of tifluadom and levallorphan to stimulate [35S]GTPgammaS binding indicates that the chiral carbon of levallorphan, a benzomorphan derivative, imparts a greater degree of stereoselectivity than does the chiral carbon in the benzodiazepine derivative tifluadom. In addition, (-)tifluadom, the less potent isomer of tifluadom, which is also a gamma-aminobutyric acidA receptor agonist, stimulated [35S]GTPgammaS binding. In contrast, d-pentazocine, (+)SKF10047, (+)cyclazocine, and d-ethylketocyclazocine displayed no agonist activity. kappaOR-selective antagonist norbinaltorphimine competitively inhibited the stimulation of [35S]GTPgammaS binding by the active isomers of ethylketocyclazocine, cyclazocine, and nalorphine to the same degree, indicating that all three ligands are eliciting an effect via the kappaOR. The results suggest that these cells express a homogeneous population of kappaOR, and that their [35S]GTPgammaS-binding properties make them an excellent means to assess kappaOR efficacy.
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PMID:Opioid efficacy in a C6 glioma cell line stably expressing the human kappa opioid receptor. 991 95

We have recently shown that endothelin-1 activates two types of Ca2+-permeable nonselective cation channels (NSCC-1 and NSCC-2) in C6 glioma cells. These channels can be distinguished by their sensitivity to blockers of the receptor-operated Ca2+ channel, 1-[b-(3-[4-methoxyphenyl]propoxy)-4-methoxyphenethyl]-1H-imidazole hydrochloride (SK&F 96365) and (R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di-[2-(2,3,4-trimethoxyphenyl)ethyl]-acetamide (LOE 908). NSCC-1 is sensitive to LOE 908 and resistant to SK&F 96365, whereas NSCC-2 is sensitive to both LOE 908 and SK&F 96365. Moreover, extracellular Ca2+ influx through these channels plays an essential role in endothelin-1-induced mitogenesis in C6 glioma cells. The purpose of the present study was to investigate the effects of extracellular Ca2+ influx on intracellular pathways of endothelin-1-induced mitogenic responses in C6 glioma cells. We focused on extracellular signal-regulated kinase 1 and 2 (ERK1/2) in this context. An inhibitor of mitogen-activated protein kinase, 2-[2-amino-3-methoxyphenyl]-4H-1-benzopyran-4-one (PD 98059), abolished the endothelin-1-induced increase in ERK1/2 activity, but only partially suppressed the mitogenic response. ERK1/2 activation by endothelin-1 was partially suppressed in the absence of extracellular Ca2+. On the basis of the sensitivity to LOE 908 and SK&F 96365, Ca2+ influx through NSCC-1 and NSCC-2 plays an essential role in the extracellular Ca2+-dependent component of ERK1/2 activity. In contrast, Ca2+ influx through NSCC-2 is involved in the ERK1/2-independent component of endothelin-1-induced mitogenesis. These results indicate that (1) the endothelin-1-induced mitogenic response involves both ERK1/2-dependent and -independent mechanisms, (2) ERK1/2 activation by endothelin-1 involves an extracellular Ca2+ influx-dependent cascade as well as an extracellular Ca2+ influx-independent cascade, (3) because endothelin-1-induced mitogenesis is completely dependent on extracellular Ca2+ influx, extracellular Ca2+ influx also plays an important role in mitogenic pathways downstream of ERK1/2, (4) extracellular Ca2+ influx through NSCC-1 and NSCC-2 has an important role in the extracellular Ca2+ influx-dependent component of ERK1/2-dependent mitogenesis, (5) extracellular Ca2+ influx through NSCC-2 has an important role in ERK1/2-independent mitogenesis, and (6) Ca2+ influx through each Ca2+ channel may play a distinct role in intracellular mitogenic cascades.
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PMID:Effects of extracellular Ca2+ influx on endothelin-1-induced intracellular mitogenic cascades in C6 glioma cells. 1182 Oct 17

Tumor hypoxia is an important prognostic indicator for cancer therapy outcome. EF5 [2-(2-nitro-1[ H]-imidazol-1-yl)- N-(2,2,3,3,3-pentafluoropropyl)-acetamide] has been employed to measure tumor hypoxia in animals and humans using immunohistochemical methods. EF5 is a lipophilic molecule designed to have a very uniform biodistribution, a feature of obvious benefit for use in PET imaging. The present study represents the first demonstration of noninvasive PET imaging of rat tumors using fluorine-18 labeled EF5. Because of the small tumor size, partial volume effects may result in underestimation of concentration of the compound. Therefore, validation of the PET data was performed by gamma counting of the imaged tissue. The tumor models studied were the Morris 7777 (Q7) hepatoma (n=5) and the 9L glioma (n=2) grown subcutaneously in rats. Our previous studies have demonstrated that early passage 9L tumors are not severely hypoxic and that Q7 tumors are characterized by heterogeneous regions of tumor hypoxia (i.e., Q7 tumors are usually more hypoxic than early passage 9L tumors). The seven rats were imaged in the HEAD Penn-PET scanner at various time points after administration of 50-100 micro Ci (18)F-EF5 in 30 mg/kg carrier nonradioactive EF5. The carrier was used to ensure drug biodistribution comparable to prior studies using immunohistochemical methods. (18)F-EF5 was excreted primarily via the urinary system. Images obtained 10 min following drug administration demonstrated that the EF5 distributed evenly to all organ systems, including brain. Later images showed increased uptake in most Q7 tumors compared with muscle. Liver uptake remained relatively constant over the same time periods. Tumor to muscle ratios ranged from 0.82 to 1.73 (based on PET images at 120 min post injection) and 1.47 to 2.95 (based on gamma counts at approximately 180 min post injection). Tumors were easily visible by 60 min post injection when the final tumor to muscle ratios (based on gamma counts) were greater than 2. Neither of the 9L tumors nor the smallest Q7 tumor met this criterion, and these tumors were not seen on the PET images. These preliminary results suggest that (18)F-EF5 is a promising agent for noninvasive assessment of tumor hypoxia. Plans are underway to initiate a research project to determine the safety and preliminary evidence for the efficacy of this preparation in patients with brain tumors.
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PMID:Noninvasive imaging of tumor hypoxia in rats using the 2-nitroimidazole 18F-EF5. 1255 44

We recently demonstrated that endothelin-1 (ET-1) activates two types of Ca(2+)-permeable nonselective cation channels (NSCC-1 and NSCC-2) in C6 glioma cells. It is possible to discriminate between these channels by using the Ca(2+) channel blockers SK&F 96365 (1-[beta-(3-[4-methoxyphenyl]propoxy)-4-methoxyphenethyl]-1H-imidazole hydrochloride) and LOE 908 [(R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di-[2-(2,3,4-trimethoxyphenyl)ethyl]-acetamide]. LOE 908 is a blocker for NSCC-1 and NSCC-2, whereas SK&F 96365 is an inhibitor for NSCC-2. The purpose of the present study was to identify the G-proteins that are involved in ET-1-activated Ca(2+) channels in C6 glioma cells. ET-1 activated only NSCC-1 in C6 glioma cells preincubated with U73122 (1-[6-[((17beta)-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl]-1H-pyrrole-2,5-dione), a phospholipase C (PLC) inhibitor. Microinjection of the dominant negative mutant of G(12)/G(13) (G(12)G228A/G(13)G225A) abolished activation of NSCC-1 and NSCC-2. In contrast, pertussis toxin did not affect any of the Ca(2+) channels in the ET-1-stimulated C6 glioma cells. These results indicate that G(12)/G(13) may couple with endothelin receptors and play an important role in the activation of NSCCs in C6 glioma cells. Moreover, the activation mechanisms of NSCC-1 and NSCC-2 by ET-1 were different. NSCC-1 activation depended upon a G(12)/G(13)-dependent cascade, whereas NSCC-2 activation depended upon both G(q)/PLC- and G(12)/G(13)-dependent cascades.
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PMID:Molecular mechanisms for the activation of Ca2+-permeable nonselective cation channels by endothelin-1 in C6 glioma cells. 1273 55

Porphobilinogen deaminase (PBGD) is a rate-limiting enzyme of the heme biosynthesis pathway, whose level is elevated in various human tumors. PBGD was observed in both nuclear and cytoplasmic fractions of C6 glioma cells by immunostaining. During mitosis, chromatids were intensely stained for PBGD in comparison to the interphase chromatin. Using the yeast two-hybrid system, we identified RanBPM, the nuclear Ran-binding protein, as an interacting partner of PBGD. During butyrate-induced differentiation of C6, both nuclear and cytoplasmic PBGD levels declined as did Ran protein and its nucleotide exchange factor RCC1. N,N'-hexamethylene bis-acetamide-dependent differentiation resulted in an increase of the cytoplasmic PBGD, whereas nuclear PBGD, Ran protein and RCC1 remained unchanged. mRNA levels of PBGD remained unchanged during stimulation with both butyrate and N,N'-hexamethylene bis-acetamide. The enzymatic activity of PBGD and protoporphyrin IX synthesis in C6 cells were dependent on the differentiation induction agent. We conclude that PBGD possibly has a nuclear role in addition to its cytosolic enzymatic activity required for heme synthesis, which is related to cell transformation and differentiation.
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PMID:A porphobilinogen deaminase (PBGD) Ran-binding protein interaction is implicated in nuclear trafficking of PBGD in differentiating glioma cells. 1291 23

We investigated the ability of N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide (AC-5216), a novel mitochondrial benzodiazepine receptor (MBR) ligand, to produce anti-anxiety and antidepressant-like effects in various animal models. AC-5216 showed high affinity for MBRs prepared from rat whole brain (Ki 0.297 nm), rat glioma cells (IC50 3.04 nm) and human glioma cells (IC50 2.73 nm), but only negligible affinity for the other main receptors including central benzodiazepine receptors. AC-5216 produced anti-anxiety effects in the Vogel-type conflict test in rats, and in the light/dark box and social interaction tests in mice at 0.1-3, 0.003-0.01 and 0.01-0.3 mg kg(-1), p.o., respectively. These effects of AC-5216 were antagonized by PK11195, an MBR antagonist. In the forced swimming test in rats, AC-5216 (3-30 mg kg(-1), p.o.) reduced the immobility time, and this effect was blocked by PK11195. AC-5216 had no myorelaxant effects, did not affect the memory or prolong hexobarbitone-induced sleep in mice, even at doses as high as 1000 mg kg(-1), p.o. Although it did slightly prolong the ethanol-induced sleep time at 1000 mg kg(-1), AC-5216 (1-100 mg kg(-1), p.o.) produced no distinct change in the rat electroencephalogram. These results indicate that AC-5216 produces anti-anxiety and antidepressant-like effects that are mediated by MBR, but does not cause the side effects normally associated with conventional benzodiazepines. Hence, AC-5216 shows potential for the treatment of stress-related disorders including anxiety and depression.
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PMID:Antianxiety and antidepressant-like effects of AC-5216, a novel mitochondrial benzodiazepine receptor ligand. 1524 20

The present paper reports the synthesis and binding studies of new 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamides as selective Peripheral Benzodiazepine Receptor (PBR) ligands. The variability of substituents at the 3-position was investigated and a 3D-QSAR model was proposed to evaluate the effect of different substitutions on the acetamide moiety. In addition, a subset of the novel compounds showing high affinity for PBR was tested for their ability to modulate the steroid biosynthesis in C6 glioma cells.
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PMID:Insight into 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamides as peripheral benzodiazepine receptor ligands: synthesis, biological evaluation and 3D-QSAR investigation. 1597 99

Herein, we report the synthesis of four new phenyl alkyl ether derivatives (7, 9-11) of the pyrazolo[1,5-a]pyrimidine acetamide class, all of which showed high binding affinity and selectivity for the TSPO and, in the case of the propyl, propargyl, and butyl ether derivatives, the ability to increase pregnenolone biosynthesis by 80-175% over baseline in rat C6 glioma cells. While these compounds fit our in silico generated pharmacophore for TSPO binding the current model does not account for the observed functional activity.
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PMID:Pyrazolo[1,5-a]pyrimidine acetamides: 4-Phenyl alkyl ether derivatives as potent ligands for the 18 kDa translocator protein (TSPO). 2072 49

Mitochondria represent an attractive subcellular target due to its function particularly important for oxidative damage, calcium metabolism and apoptosis. However, the concept of mitochondrial targeting has been a neglected area so far. The translocator protein (TSPO) represents an interesting subcellular target not only to image disease states overexpressing this protein, but also for a selective mitochondrial drug targeting. Recently, we have delivered in vitro and in vivo small molecule imaging agents into cells overexpressing TSPO by using a family of high-affinity conjugable ligands characterized by 2-phenyl-imidazo[1,2-a]pyridine acetamide structure. As an extension, in the present work we studied the possibility to target and image TSPO with dendrimers. These nano-platforms have unique features, in fact, are prepared with a level of control not reachable with most linear polymers, leading to nearly monodisperse, globular macromolecules with a large number of peripheral groups. As a consequence, they are an ideal delivery vehicle candidate for explicit study of the effects of polymer size, charge, composition, and architecture on biologically relevant properties such as lipid bilayer interactions, cytotoxicity, cellular internalization, and subcellular compartments and organelles interactions. Here, we present the synthesis, characterization, cellular internalization, and mitochondria labeling of a TSPO targeted fourth generation [G(4)-PAMAM] dendrimer nanoparticle labeled with the organic fluorescent dye fluorescein. We comprehensively studied the cellular uptake behavior of these dendrimers, into glioma C6 cell line, under the influence of various endocytosis inhibitors. We found that TSPO targeted-G(4)-PAMAM-FITC dendrimer is quickly taken up by these cells by endocytosis pathways, and moreover specifically targets the mitochondria as evidenced from subcellular fractionation experiments and co-localization studies performed with CAT (Confocal-AFM-TIRF) microscopy.
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PMID:In vitro targeting and imaging the translocator protein TSPO 18-kDa through G(4)-PAMAM-FITC labeled dendrimer. 2409 15


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