Binding Ability Of Receptor Research Articles

Pharmacological Analysis of GABAA Receptor and Sigma1R Chaperone Interaction: Research Report I-Investigation of the Anxiolytic, Anticonvulsant and Hypnotic Effects of Allosteric GABAA Receptors' Ligands.

Two groups of facts have been established in previous drug development studies of the non-benzodiazepine anxiolytic fabomotizole. First, fabomotizole prevents stress-induced decrease in binding ability of the GABAA receptor's benzodiazepine site. Second, fabomotizole is a Sigma1R chaperone agonist, and exposure to Sigma1R antagonists blocks its anxiolytic effect. To prove our main hypothesis of Sigma1R involvement in GABAA receptor-dependent pharmacological effects, we performed a series of experiments on BALB/c and ICR mice using Sigma1R ligands to study anxiolytic effects of benzodiazepine tranquilizers diazepam (1 mg/kg i.p.) and phenazepam (0.1 mg/kg i.p.) in the elevated plus maze test, the anticonvulsant effects of diazepam (1 mg/kg i.p.) in the pentylenetetrazole-induced seizure model, and the hypnotic effects of pentobarbital (50 mg/kg i.p.). Sigma1R antagonists BD-1047 (1, 10, and 20 mg/kg i.p.), NE-100 (1 and 3 mg/kg i.p.), and Sigma1R agonist PRE-084 (1, 5, and 20 mg/kg i.p.) were used in the experiments. Sigma1R antagonists have been found to attenuate while Sigma1R agonists can enhance GABAARs-dependent pharmacological effects.

Ferrocene Macrocyclic Schiff Base Complex: Synthesis, Structure and Recognition Properties for Dual Hg2+ and Cu2+

A probe based on ferrocene structure has been designed, synthesized and elucidated from the single crystal X-ray method. It demonstrated fluorescence response to Hg2+ and Cu2+ in CH3OH. The results indicated that the title complex could be applied in the multianalyte detection. Binding ability of receptor 3 in CH3OH was tested for various cations (Fe3+, Co2+, Cu2+, Zn2+, Cd2+, Hg2+, Pb2+, and Ba2+ in water). The computed binding constants for Hg2+ and Cu2+ indicated a distinct absorbance shift. The receptor is an attractive array due to its distinct absorbance shift profile in a semi-aqueous phase, making it applicable in biology, environmental sciences and material chemistry.

1,9-Dicarbonyl-2,8-dioxo-butyne-ester Ferrocenophane: Synthesis, Structure and Recognition Properties for Co2+ and Cu2+ Ions

An efficient highly diluted synthetic approach to the synthesis of 1,9-dicarbonyl-2,8-dioxo-butyne ester ferrocenophane (L) has been developed. The title compound was characterized by IR, UV, FL, 1H NMR, spectroscopies, elemental analysis and so on. Further complex L shows fluorescence responses to Co2+ and Cu2+ in CH3OH, The results indicate that the complex could be applied in multianayte detection. The binding ability of receptor L CH3OH was tested for various cations (Co2+, Cu2+, Zn2+, and Ni2+ in water) and the binding constants for Co2+ and Cu2+ were the computed, having a distinct absorbance shift. The receptor is a very attractive array because its distinct absorbance shift profile in a semi-aqueous phase, making it applicable in the area of biology, environmental sciences and material chemistry.

Glucocorticoids regulate MiR-29c levels in vascular smooth muscle cells through transcriptional and epigenetic mechanisms

AimsThe objective of this study was to determine the underlying mechanism by which glucocorticoids (GCs) induce of miR-29c expression in vascular smooth muscle cells. Main methodsQRT-PCR was used for miR-29c detection. Protein levels were determined by western blotting. Knockdown of SP1, DNMT1 and DNMT3A was achieved through transfection with their specific respective siRNAs. The effect of GCs on SP1 activity was determined by luciferase reporter assay and the methylation status in miR-29c promoter was detected by methylation specific PCR. CHIP assay was used to determine the binding ability of SP1 and glucocorticoid receptor (GR) in miR-29c promoter. Key findingsTreatment of RASMC with SP1 siRNA or SP1 inhibitor, mithramycin A, as well as DNMT1 and DNMT3A siRNAs and an inhibitor of DNMTs, Decitabine, resulted in increased expression of miR-29c (P<0.05). Treatment RASMC with dexamethasone (DEX, 0.1μM) for 24h reduced the expression of SP1 and phosphorylated SP1 at threonine 453 protein levels, repressed SP1 activity, and inhibited the expression of DNMT1 and DNMT3A proteins (P<0.05). Treatment with mifepristone, a GR antagonist, blocked the inhibitory effect of DEX on DNMT1 and DNMT3A protein expression. DEX also suppressed SP1 binding ability in miR-29c promoter and inhibited methylation of miR-29c promoter (P<0.05). Treatment of RASMC with DEX (0.1μM) significantly (P<0.05) increased the binding of GR to the miR-29c promoter. SignificanceThe stimulatory effect of GCs on miR-29c expression is mediated by these three mechanisms: transcriptionally regulated by SP1, and epigenetically through a methylation-dependent process and GR.

Synthesis of bifunctional receptor for fluoride and cadmium based on calix[4]arene with thiourea moieties

A new calix[4]arene thiourea derivative bearing a benzothiazolyl moiety (L) was synthetized and characterized by single crystal X-ray, NMR and ESI-TOF. The binding ability of the bifunctional receptor towards several ions was investigated in acetonitrile by means of UV–Visible and NMR spectroscopy. The UV–Vis studies of receptor L demonstrated a stoichiometry of 1:1 for all ions studied. Also, recognize selectively F− and Cd2+ with a detection limit of 97 and 37 μM, respectively.Also, 1H NMR titration of receptor L indicated that both thiourea bridge and phenolic hydroxyl functional groups played a critical role in the binding of F− and Cd2+ ions. 1H NMR spectrum showed that receptor L has a flattened-cone conformation in solution that changes to a cone conformation in the presence of fluoride while cadmium maintained the initial conformation.

PP2A inhibitors induce G2/M cell cycle arrest in pancreatic cancer cells through JNK pathway

The objective of this study was to determine the underlying mechanism by which glucocorticoids (GCs) induce of miR-29c expression in vascular smooth muscle cells.QRT-PCR was used for miR-29c detection. Protein levels were determined by western blotting. Knockdown of SP1, DNMT1 and DNMT3A was achieved through transfection with their specific respective siRNAs. The effect of GCs on SP1 activity was determined by luciferase reporter assay and the methylation status in miR-29c promoter was detected by methylation specific PCR. CHIP assay was used to determine the binding ability of SP1 and glucocorticoid receptor (GR) in miR-29c promoter.Treatment of RASMC with SP1 siRNA or SP1 inhibitor, mithramycin A, as well as DNMT1 and DNMT3A siRNAs and an inhibitor of DNMTs, Decitabine, resulted in increased expression of miR-29c (P < 0.05). Treatment RASMC with dexamethasone (DEX, 0.1 μM) for 24 h reduced the expression of SP1 and phosphorylated SP1 at threonine 453 protein levels, repressed SP1 activity, and inhibited the expression of DNMT1 and DNMT3A proteins (P < 0.05). Treatment with mifepristone, a GR antagonist, blocked the inhibitory effect of DEX on DNMT1 and DNMT3A protein expression. DEX also suppressed SP1 binding ability in miR-29c promoter and inhibited methylation of miR-29c promoter (P < 0.05). Treatment of RASMC with DEX (0.1 μM) significantly (P < 0.05) increased the binding of GR to the miR-29c promoter.The stimulatory effect of GCs on miR-29c expression is mediated by these three mechanisms: transcriptionally regulated by SP1, and epigenetically through a methylation-dependent process and GR.

Triazolyl Alkoxy Fischer Carbene Complexes in Conjugation with Ferrocene/Pyrene as Sensory Units: Multifunctional Chemosensors for Lead(II), Copper(II), and Zinc(II) Ions

The regioselective 1,3-dipolar cycloaddition reaction of alkoxy alkynyl Fischer carbene complex 1 with azidomethyl ferrocene 2 and with azidomethyl pyrene 4 under solvent-free conditions yielded the triazolyl Fischer carbene complexes 3 (C27H21O6N3FeW) and 5 (C33H21O6N3W), respectively. The cation complexation properties of these receptors have been systematically studied using electrochemical and spectroscopic techniques. The exceptional structural feature existing in these receptors is the presence of a Fischer carbene moiety, connected to the ferrocene or pyrene moiety through a 1,2,3-triazole ring. Receptor 3 contains a redox-active ferrocene moiety and is highly selective toward Pb2+ ion, whereas receptor 5, having a fluorescent pyrene unit, selectively recognizes Zn2+ and Cu2+ ions. The binding ability of receptor 3 can be inferred either from the redox shift (the anodic shift ΔE1/2 = 55 mV) or the highly visual output response for Pb2+ ion. Receptor 5 displays considerable chelation-enhanced fluore...

An efficient triazole-based fluorescent “turn-on” receptor for naked-eye recognition of F− and AcO−: UV–visible, fluorescence and 1H NMR studies

An efficient colorimetric receptor was developed by a simple convenient method which exhibited naked-eye sensitivity for fluoride and acetate in a biologically competing solvent like DMSO. The receptor developed, portrayed a substantial change in the UV–visible absorption characteristics upon addition of fluoride and acetate anions over other anions. The binding constants showed that the binding ability of receptor towards F− anion was slightly higher than that of the AcO− anion. Job's plots indicated the formation of a (1:1) complex (receptor:anion) of receptor with fluoride and acetate anions respectively. A “turn on” fluorescence response with a red shift was observed upon fluorescence titration. 1H NMR titration experiments revealed the mechanism to be driven by the hydrogen bonding interaction of amide NH and phenol OH of the receptor molecule which was followed by deprotonation in the receptor by the F− and AcO− anions.

Synthesis and photophysical properties of 2,2′-binaphthalene-based receptor bearing trimethylsilyl groups to improve the solubility

Two trimethylsilyl groups were introduced at 5- and 5′-positions of 2,2′-binaphthalene to improve the solubility of 2,2′-binaphthalene-based receptors. The X-ray crystallographic analysis revealed the twisted structure of 2 in the solid state. The solubility of 2 was moderately improved by 3.1-fold comparing with mother skeleton 1. As a practical example of 2, receptor 8 bearing two aza-15-crown-5 moieties was prepared and the selective binding of 8 with Ba2+ can be observed by the formation of sandwich-like complex, which shows no prevention of binding ability of the receptor by introduction of the bulky substituents.

A highly selective colorimetric probe based on 2,2′,2″-trisindolylmethene for cysteine/homocysteine

The interaction and colorimetric sensing properties of receptor 1, tris(3-methylindole-2-yl)methene as the perchlorate salt, with amino acids in aqueous MeCN at neutral pH were investigated using UV–vis spectroscopic techniques. Specifically, receptor 1 behaves as a colorimetric probe for selective and sensitive detection of cysteine (Cys)/homocysteine (Hcy) based on the nucleophilic addition reaction between the sulphydryl group of Cys/Hcy and the meso carbon–carbon double bond of receptor 1, leading to clear color change from violet to colorless. A more quantitative determination for Cys/Hcy was preliminary performed by flow injection analysis (FIA) coupled with spectrophotometry. The selective binding ability of receptor 1 toward Cys/Hcy has also been evaluated by electrochemical techniques.

Evaluation of the binding ability of a macrobicyclic receptor for anions by potentiometry and molecular dynamics simulations in solution

Abstract The macrobicycle derived from bis-tren and containing diphenoxy groups as spacers, L1, was synthesized and used as receptor for anions. The binding ability of the new receptor for some aromatic carboxylates [phthalate (ph2−), isophthalate (iph2−), terephthalate (tph2−), benezenetricarboxylate (btc3−), and the herbicide 4-amino-3,5,6-trichloro-2-pyridinecarboxylate (ATCP−)], and the aliphatic cyclohexanetricarboxylate (ch3−) anions was evaluated by potentiometric measurements and molecular dynamic simulation in solution. The association constants were determined by potentiometry in H2O/MeOH (1:1 v/v) at 298.2 K and 0.10 mol dm−3 in KCl. The strongest association was found with btc3− anion and the effective binding constants at pH 5.5 follow the order: btc3−>tph2−>ph2−≈iph2−>ch3−≈ATCP−. Molecular dynamics simulations carried out for the associations of (H6L1)6+ with btc3−, tph2− and iph2− in the same mixture of solvents indicated that these anions interact with the receptor by a combination of electrostatic and multiple N–H⋯O C hydrogen bond interactions. It was also verified that in the recognition process the tph2− remained encapsulated over the entire time of simulation while the btc3− is partially inserted into the receptor cavity with one carboxylate group largely exposed to water solvent molecules, and iph2− anion exhibited an intermediate binding behaviour. The free energy difference between btc3− and iph2− associations estimated by free energy calculations is in excellent agreement with the difference found from the experimental values for the corresponding association constants, which indicates that the unconstrained molecular dynamics simulations carried out with these two anions are realistic pictures of their molecular recognition processes.

Visual distinction of dicarboxylic acids and their salts by 1-phenyl-3-(quinolin-5-yl)urea

The ability to recognize dicarboxylic acids by 1-phenyl-3-(quinolin-5-yl)urea ( I) as a receptor is studied. The solution studies on receptor binding with various dicarboxylic acids show salt and co-crystal formation by I with different dicarboxylic acids. The salts and co-crystals can be distinguished by visible spectroscopy. The crystal structures of five such salts or co-crystals of I with maleic acid, fumaric acid, malonic acid, 1,4-phenylenediacetic acid and pyridine 2,3-dicarboxylic acid are determined. A similar isomeric compound 1-phenyl-3-(quinolin-8-yl)urea ( II) is a receptor for mineral acids, but it is not suitable for binding to dicarboxylic acids. The advantage of higher binding ability of receptor I over II with maleic acid provides not only a means for separation of fumaric acid from maleic acid but also helps in separation of mixture of the receptor I and II.

Ratiometric Fluorescence Sensing of Fluoride Ions by an Asymmetric Bidentate Receptor Containing a Boronic Acid and Imidazolium Group

AbstractThe synthesis of the first examples of anion receptors that utilize boron–fluoride interactions and (C–H)+···F–‐type ionic hydrogen‐bond interactions in the binding of F ions is reported herein. o‐, m‐, and p‐Phenylboronic acids were linked to naphthoimidazolium through a methylene group. On the basis of fluorescence and 19F NMR studies, we have confirmed that the addition of fluoride to a boron center occurs prior to the formation of (C–H)+···F–‐type ionic hydrogen bond with the imidazolium moiety. More importantly, these investigations have demonstrated that only the receptor bearing the ortho‐directed boron and imidazolium exhibits enhanced fluoride binding. The increased binding ability of the asymmetric bidentate receptor of ortho‐boronic acid and imidazolium towards F– enables it to sense fluoride ions in a 95:5 CH3CN/HEPES aqueous solution. The fluorescence responses to different anions were also explored; the ortho‐boron‐imidazolium receptor displayed ratiometric fluorescence changes and a high selectivity towards fluoride ions over other anions (Cl–, Br–, CH3CO2–, HSO4–, and H2PO4–).(© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2009)

The anion recognition properties of Schiff base or its reductive system based on 2,2′-bipyridine derivatives

Two novel artificial receptors, 2,2′-bipyridine derivatives containing phenol group, have been designed and synthesized. The interaction of the receptors containing Schiff base or its reductive system with biologically important anions was determined by UV–vis and 1H NMR titration experiments. Results indicate that receptors 1 and 2 show the strong binding ability for dihydrogen phosphate (H 2PO 4 −), fluoride (F −), acetate (AcO −) and almost no binding ability for chloride (Cl −), bromide (Br −), iodide (I −). At the same time, the strongest binding ability of receptor 1 for H 2PO 4 − among studied anions is not influenced by the existence of other anions; as well as receptor 2 for F −. In addition, the binding ability of receptor 1 (Schiff base system) with various anions is stronger than that of receptor 2 (the reductive Schiff base system) due to the difference of electronic effect.

A Novel Acetate Selective UV‐Vis Chemosensor Containing a Tripodal Benzaldehydic‐phenylhydrazone

AbstractA new colorimetric chemosensor 1 based on a tripodal benzaldehydic‐phenylhydrazone selectively sensing acetate ion has been synthesized. The highly selective binding ability of receptor 1 to acetate ion over other studied anions was demonstrated by UV‐Vis absorption spectroscopy in DMSO. Compared with other anions studied, its UV/Vis absorption spectrum in DMSO shows response towards the presence of acetate ion with high selectivity, and also color change from yellow to blue in the presence of acetate ion (2×10−5 mol·dm−3). Little UV/Vis absorption spectrum change has occurred when receptor 1 was treated with other different guest anions (F−, Cl−, Br−, I−, H2PO4− and OH−). The Kass of receptor 1 binding with acetate ion is 1.69×104.

Study on Synthesis and Binding Ability of a New Anion Receptor Containing NH Binding Sites

AbstractA new colorimetric recognition receptor 1 based on the dual capability containing NH binding sites of selectively sensing anionic guest species has been synthesized. Compared with other halide anions, its UV/Vis absorption spectrum in dimethyl sulfoxide showed the response toward the presence of fluoride anion with high selectivity, and also displayed dramatic color changes from colorless to yellow in the presence of TBAF (5×10−5 mol/L). The similar UV/Vis absorption spectrum change also occurred when 1 was treated with AcO− while a little change with H2PO−4 and OH−. Receptor 1 has almost not affinity abilities to Cl−, Br− and I−. The binding ability of receptor 1 to fluoride with high selectivity over other halides contributes to the anion size and the ability of forming hydrogen bonding. While the different ability of binding with geometrically triangular (AcO−), tetrahedral (H2PO−4) and linear (OH−) anions maybe result from their geometry configuration.

Evaluation of the Binding Ability of a Novel Dioxatetraazamacrocyclic Receptor that Contains Two Phenanthroline Units: Selective Uptake of Carboxylate Anions

The novel dioxatetraaza macrocycle [26]phen2N4O2, which incorporates two phenanthroline units, has been synthesized, and its acid-base behavior has been evaluated by potentiometric and 1H NMR methods. Six protonation constants were determined, and the protonation sequence was established by NMR. The location of the fifth proton on the phen nitrogen was confirmed by X-ray determinations of the crystal structures of the receptor as bromide and chloride salts. The two compounds have the general molecular formula {(H5[26]phen2N4O2)Xn(H2O)(5-n)}X(n-1) x mH2O, where X = Cl, n = 3, and m = 6 or X = Br, n = 4, and m = 5.5. In the solid state, the (H5[26]phen2N4O2)(5+) cation adopts a "horseshoe" topology with sufficient room to encapsulate three or four halogen anions through the several N-H...X hydrogen-bonding interactions. Two supermolecules {(H5[26]phen2N4O2)Xn(H2O)5-n}(5-n)(+) form an interpenetrating dimeric species, which was also found by ESI mass spectrum. Binding studies of the protonated macrocycle with aliphatic (ox(2-), mal(2-), suc(2-), cit(3-), cta(3-)) and aromatic (bzc(-), naphc(-), anthc(-), pyrc(-), ph(2-), iph(2-), tph(2-), btc(3-)) anions were determined in water by potentiometric methods. These studies were complemented by 1H NMR titrations in D2O of the receptor with selected anions. The Hi[26]phen2N4O2(i+) receptor can selectively uptake highly charged or extended aromatic carboxylate anions, such as btc(3-) and pyrc(-), in the pH ranges of 4.0-8.5 and <4.0, respectively, from aqueous solution that contain the remaining anions as pollutants or contaminants. To obtain further insight into these structural and experimental findings, molecular dynamics (MD) simulations were carried out in water solution.

A Tricatecholic Receptor for Carbohydrate Recognition: Synthesis and Binding Studies

A new tripodal receptor bearing three catechol subunits on a benzene platform has been synthesized in four steps from 1,3,5-triethylbenzene and pyrogallol. The binding ability of the tricatecholic receptor was investigated toward several monosaccharides in CDCl3, where multiple equilibria were detected, and compared to that of a previously reported trisureidic receptor of analogous structure. Association constants were measured by 1H NMR titrations, and the corresponding affinities were assessed through the BC50 parameter, a binding descriptor univocally defining the affinity of a host for a guest in multi-equilibrium systems. Results show that the tripodal catecholic receptor binds the octyl glycosides with affinities ranging from 0.87 to 5.2 mM and with a 6-fold selectivity factor for the alpha-mannoside over the beta-glucoside. Although the affinity for glycosides was not appreciably improved with respect to the ureidic receptor, a significant change in selectivity was obtained by the H-bonding group replacement.

Structural Effects on the Ground and Excited-state Properties of Photoswitchable Hydrogen-Bonding Receptors

The ground- and excited-state properties of a series of photochromic barbiturate receptors (N,N'-bis{6-[omega-(anthracen-9-yloxy)alkanoylamino]pyridin-2-yl}-5-t-butyl-isophthalamide, Tn), in which anthracene chromophores are tethered via (CH2)n (n = 1, 3-6) polymethylene linkers to the H-bond receptor moiety, are described. In these systems, the thermally reversible [4pi + 4pi] photodimerization of the anthracenes yields macrocyclic receptors (TnC) that possess significantly reduced affinity toward barbital as compared to their acyclic counterparts. The length of the tether not only determines the overall binding ability of the cyclized receptor but also has a profound influence on the photochemical and photophysical properties of the anthracene chromophores. The reduced mobility experienced by the covalently bound anthracenes controls the reactivity of a fluorescent excimer that is proposed to be an intermediate in the photocyclization process.

Glycosylation processing inhibition by castanospermine prevents experimental autoimmune encephalomyelitis by interference with IL-2 receptor signal transduction

In this study, we explored the therapeutic targets of the glycosylation processing inhibitor, castanospermine (CAST), in murine passive transfer experimental autoimmune encephalomyelitis (EAE), a model disease of multiple sclerosis. By using lymphocytic–endothelial adhesion and transmigration assays, FACScan and Western blotting, we defined the effects of CAST on expression, function and signal transduction of glycoproteins crucial in the pathophysiology of this disease. CAST prevented clinical signs of EAE and completely inhibited inflammatory CNS infiltrates associated with this disease. Here, we showed that CAST blocks antigen-induced lymphocytic activation and clonal expansion in a dose-dependent manner. Importantly, we observed that CAST strongly impairs IL-2-induced signal transduction of the IL-2 receptor. In contrast, neither expression nor binding ability of the IL-2 receptor was affected by this drug. In addition, we were able to exclude major effects of CAST on expression and function of different glycoproteins important in antigen presentation as well as lymphocytic–endothelial adhesion and transmigration. In conclusion, CAST strongly interferes in the signal transduction of the IL-2 receptor. This could explain both inhibitory effects of CAST in clonal T cell expansion and development of transfer EAE. This relatively selective pharmacological effect of CAST highlights its potential as a novel immunomodulatory approach in multiple sclerosis.