Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity

Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl) benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenyl-ethynyl)-pyridine (MPEP) binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate phen-cyclidine-induced hyperlocomotor activity. (4-Hydroxypiperidin-1-yl)(4-phenylethynyl) phenyl) methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl) ethynyl) nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders.

Tetrahexahedral Pt Nanocrystal Catalysts Decorated with Ru Adatoms and Their Enhanced Activity in Methanol Electrooxidation

Tetrahexahedral Pt nanocrystals (THH Pt NCs) bound by well-defined high index crystal planes offer exceptional electrocatalytic activity, owing to a high density of low-coordination surface Pt sites. We report, herein, on methanol electrooxidation at THH Pt NC electrodes studied by a combination of electrochemical techniques and in situ FTIR spectroscopy. Pure THH Pt NC surfaces readily facilitate the dissociative chemisorption of methanol leading to poisoning by strongly adsorbed CO. Decoration of the stepped surfaces by Ru adatoms increases the tolerance to poisoning and thereby reduces the onset potential for methanol oxidation by over 100 mV. The Ru modified THH Pt NCs exhibit greatly superior catalytic currents and CO2 yields in the low potential range, when compared with a commercial PtRu alloy nanoparticle catalyst. These results are of fundamental importance in terms of model nanoparticle electrocatalytic systems of stepped surfaces and also have practical significance in the development of surface tailored, direct methanol fuel cell catalysts.

Cold-formed steel sections with web openings subjected to web crippling under two-flange loading conditions - Part II: Parametric study and proposed design equations

A parametric study of cold-formed steel sections with web openings subjected to web crippling was undertaken using finite element analysis, to investigate the effects of web holes and cross-section sizes on the web crippling strengths of channel sections subjected to web crippling under both interior-two-flange (ITF) and end-two-flange (ETF) loading conditions. In both loading conditions, the hole was centred beneath the bearing plate. It was demonstrated that the main factors influencing the web crippling strength are the ratio of the hole depth to the flat depth of the web, and the ratio of the length of bearing plates to the flat depth of the web. In this paper, design recommendations in the form of web crippling strength reduction factors are proposed, that are conservative to both the experimental and finite element results.

Synthesis of mesoporous tungsten carbide-supported platinum and its electrocatalytic activity for methanol oxidation

High activity and stability during oxidation of methanol under the relatively anode environment are two main evaluation criterias for an effective anode electrocatalyst in direct methanol fuel cell (DMFC). Mesoporous WC samples with hollow structure were prepared by gas-solid reaction at the atmosphere of CH(4)/H(2) by using airflow spray dried ammonium metatungstate (AMT). The platinum supported on this material by impregnation-vapor phase deoxidation method served as a less expensive electro anode catalyst. XRD and SEM results showed that Pt particles were well dispersed on the surface of WC. The results showed that the Pt/WC-PME exhibited an attractive catalytic activity, and methanol oxidation process in Pt/WC-PME is affected by liquid-phase mass transfer. The results also indicated that the oxidation can be improved by raising temperatures.

Detection of visual-field deterioration by Glaucoma Progression Analysis and Threshold Noiseless Trend programs

BACKGROUND: To compare the ability of Glaucoma Progression Analysis (GPA) and Threshold Noiseless Trend (TNT) programs to detect visual-field deterioration.

METHODS: Patients with open-angle glaucoma followed for a minimum of 2 years and a minimum of seven reliable visual fields were included. Progression was assessed subjectively by four masked glaucoma experts, and compared with GPA and TNT results. Each case was judged to be stable, deteriorated or suspicious of deterioration

RESULTS: A total of 56 eyes of 42 patients were followed with a mean of 7.8 (SD 1.0) tests over an average of 5.5 (1.04) years. Interobserver agreement to detect progression was good (mean kappa = 0.57). Progression was detected in 10-19 eyes by the experts, in six by GPA and in 24 by TNT. Using the consensus expert opinion as the gold standard (four clinicians detected progression), the GPA sensitivity and specificity were 75% and 83%, respectively, while the TNT sensitivity and specificity was 100% and 77%, respectively.

CONCLUSION: TNT showed greater concordance with the experts than GPA in the detection of visual-field deterioration. GPA showed a high specificity but lower sensitivity, mainly detecting cases of high focality and pronounced mean defect slopes.