Amount Of Excess Ligand Research Articles

The Impact of Excess Ligand on the Retention of Nonionic, Linear Gadolinium-Based Contrast Agents in Patients With Various Levels of Renal Dysfunction: A Review and Simulation Analysis

The role of gadolinium (Gd)-based contrast agents (GBCAs) in the pathophysiology of nephrogenic systemic fibrosis (NSF) is now uncontested. Although the definitive mechanism has not been established, the association with weaker GBCA ligands and with reduced renal clearance supports a hypothesis that Gd release from the GBCAs is a key process in precipitating the disease. Prevention strategies often include the use of more stable GBCA ligands in patients with reduced kidney function, but animal models and some clinical data suggest that better patient outcomes can be achieved when excess ligand is administered with weaker GBCAs; this is particularly significant for OptiMARK, which contains a nonionic, linear ligand similar to gadodiamide, the active ingredient in Omniscan, but contains twice the amount of excess ligand. Here we review evidence regarding the use of OptiMARK over Omniscan for prevention of NSF and perform a pharmacokinetic-based simulation to determine if the presented evidence is consistent with the established kinetics of GBCAs and Gd.

Binding of Endogenous Cannabinoid Ligand 2-Arachidonoylglycerol to Cannabinoid Receptor CB2 via the Lipid Matrix

Endogenous cannabinoid ligand, 2-arachidonoylglycerol (2-AG), binds to and activates cannabinoid type-2 receptor CB2, controlling a variety of immune and hematopoietic cellular functions. Due to the high lipophilicity of cannabinoid ligands, there have been extensive discussions that after nonspecific incorporation into membrane, approach of the ligands to the binding pocket of CB2 may take place via lateral diffusion in lipid matrix. While previously reported microsecond-long molecular dynamics simulations showed molecular details in favor of this mechanism, no in-situ experimental evidence for the binding event has yet been made. Here we report on 2H NMR results that show exchange of deuterated 2-AG-d5 between the ligand binding site on CB2 and the surrounding lipid matrix at physiological conditions. Purified, recombinant CB2 was functionally reconstituted into liposomes containing four-fold molar excess of 2-AG-d5, and its deuterium resonances measured over the temperature range of 5-20°C. When the membranes contained CB2, the ligand resonances shifted upfield by 0.5 ppm and broadened significantly. Despite the excess amount of ligand, only one set of time-averaged resonances of the ligand was observed. The result suggests that 2-AG undergoes exchange between receptor-bound and free states on millisecond timescale. The resonance linewidth decreased with decreasing temperature as predicted from reduced exchange rates. The receptor binding was specific since only well-resolved signal of 2-AG in lipid matrix was observed when the binding pocket was blocked with a high affinity synthetic agonist CP-55,940. The experiments contrast to our previous experiments on CP-55,940 binding, where the free state of 2H-labeled CP-55,940-d6 in lipid matrix showed a highly-resolved signal under much slower exchange rate. The present work emphasizes the critical role of lipid matrix to provide a pathway and to regulate approach of lipophilic cannabinoid ligands to the receptor binding pocket.

Development and evaluation of a novel radioiodinated vesamicol analog as a sigma receptor imaging agent

BackgroundSigma receptors are highly expressed in human tumors and should be appropriate targets for developing tumor imaging agents. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-pIV), with a high affinity for sigma receptors and prepared radioiodinated (+)-pIV. As a result, (+)-[125I]pIV showed high tumor uptake in biodistribution experiments. However, the accumulation of radioactivity in normal tissues, such as the liver, was high. We supposed that some parts of the accumulation of (+)-pIV in the liver should be because of its high lipophilicity, and prepared and evaluated a more hydrophilic radiolabeled vesamicol analog, (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol ((+)-IV-OH).Methods(+)-[125I]IV-OH was prepared by the chloramine T method from the precursor. The partition coefficient of (+)-[125I]IV-OH was measured. Biodistribution experiments were performed by intravenous administration of a mixed solution of (+)-[125I]IV-OH and (+)-[131I]pIV into DU-145 tumor-bearing mice. Blocking studies were performed by intravenous injection of (+)-[125I]IV-OH mixed with an excess amount of ligand into DU-145 tumor-bearing mice.ResultsThe hydrophilicity of (+)-[125I]IV-OH was much higher than that of (+)-[125I]pIV. In biodistribution experiments, (+)-[125I]IV-OH and (+)-[131I]pIV showed high uptake in tumor tissues at 10-min post-injection. Although (+)-[131I]pIV tended to be retained in most tissues, (+)-[125I]IV-OH was cleared from most tissues. In the liver, the radioactivity level of (+)-[125I]IV-OH was significantly lower at all time points compared to those of (+)-[131I]pIV. In the blocking studies, co-injection of an excess amount of sigma ligands resulted in significant decreases of tumor/blood uptake ratios after injection of (+)-[125I]IV-OH.ConclusionsThe results indicate that radioiodinated (+)-IV-OH holds a potential as a sigma receptor imaging agent.

Hydrothermal synthesis of hierarchical TiO2 microspheres using a novel titanium complex coordinated by picolinic acid

Phase- and morphology-control of TiO2 was performed by a facile hydrothermal method using a novel water-soluble titanium–picolinato complex as a precursor. Single-phase rutile or brookite type titania can be obtained by tailoring the pH of the complex solution. Rutile with a hierarchical microstructure was synthesized using an excess amount of ligand as an additive and the final product consisted of microspheres with mesopores formed by a self-assembly of nanorods. The anisotropic growth of nanorods with a high aspect ratio was explained by a capping mechanism.

Removal of Heavy Metals from Aqueous Solutions by Precipitation-Filtration Using Novel Organo-Phosphorus Ligands

An organophosphorus mixture of sodium mono- and di-(n-hexa-decyl) phosphinate was synthesized and purified, and then used as a ligand to remove heavy metals by precipitation from aqueous nitrate, chloride, and sulfate solutions. The new ligand offers more advantages over the previously studied sodium dioctyl and dodecyl phosphinates. The sodium form of the mono- and di-(n-hexa-decyl) phosphinate has a much lower solubility in water, which contributed to much lower back contamination and much lower loss of the reagent, even when excess amount of ligand was employed. Moreover, an excess amount of the ligand did not alter the filtration characteristics of the resultant precipitate. The heavy metals: lead, cadmium, mercury, cobalt, and nickel were precipitated with the sodium mono- and di-(n-hexa-decyl) phosphinate, NaL, in the form of Pb L 2(s), Cd L 2(s), Hg L 2(s), Co L 2(s), and Ni L 2(s). In the absence of free acid in the feed, a maximum removal of each metal corresponded to the stoichiometric ratio. The residual concentrations of each of the metals at the optimum conditions were measured for the different media and found to be lower than 10 ppb, lower than the acceptable levels for most regions. Lead, as a model heavy metal, was studied in more detail. Adding an acid to the feed solution reduced the removal of lead as some of the phosphinate ligand was converted to the acid form. The presence of chloride and sulfate in the feed solution; up to mole ratios to lead of 5000, and of calcium in the feed solution; up to mole ratio to lead of 200, had no effect on the removal of lead. The ligand was more selective to lead than the other four metals, and the selectivity was in the order Pb > Cd > Co & Ni > Hg. The ligand was regenerated up to 99.99% and the metals were recovered in 100 times more concentrated aqueous solutions.

ChemInform Abstract: Design of Optically Active Hydroxamic Acids as Ligands in Vanadium-Catalyzed Asymmetric Epoxidation.

New optically active hydroxamic acids bearing a 1,1′-binaphthyl group were prepared as ligands in a vanadium-catalyzed asymmetric epoxidation. The feature of these hydroxamic acids is a sterically hindered ligand. The asymmetric epoxidation with good selectivity and reactivity can be established by using VO(O-i-Pr)3 (5 mol%) and a small excess amount of ligand (7.5 mol%) with triphenylmethyl hydroperoxide (TrOOH) in toluene at -20 °C. Disubstituted allyl alcohols were epoxidized more rapidly than mono- or tri-substituted allyl alcohols, and were obtained in good to high enantioselectivities (48—94%ee). The transition state based on X-ray crystal structure of 1e is discussed.

Transformation of NIH 3T3 Cells by HER3 or HER4 Receptors Requires the Presence of HER1 or HER2

Members of the epidermal growth factor receptor (EGFR) subfamily of receptor protein tyrosine kinases have been implicated in the pathogenesis of various malignancies. The ability of one EGFR subfamily member to influence, or function synergistically with, another is likely to be a general feature of these receptors. To assess the role of receptor heterodimerization, we analyzed the ability of Neu differentiation factor (NDF) to induce cell growth and transformation of NIH 3T3 cells transfected with different combinations of the EGFR subfamily of receptors. NDF induced mitogenesis, but not transformation, of cells expressing either HER3 or HER4 alone. However, NDF-induced cell transformation was observed when either HER1 or HER2 was coexpressed with HER3 or HER4. In analogous receptor phosphorylation experiments, NDF-induced transphosphorylation appears to be correlated with synergistic transformation of NIH 3T3 cells. Interestingly, transphosphorylation between HER1 and HER4 can be stimulated by either EGF or NDF.