Harmonic Generation up to Fifth Order from Al/Au/CuS Nanoparticle Films.

Dual heterostructures integrating noble-metal and copper chalcogenide nanoparticles have attracted a great deal of attention in nonlinear optics, because coupling of their localized surface plasmon resonances (LSPRs) substantially enhances light-matter interactions through local-field effects. Previously, enhanced cascaded third-harmonic generation was demonstrated in Au/CuS heterostructures mediated by harmonically coupled surface plasmon resonances. This suggests a promising approach for extending nonlinear enhancement to higher harmonics by adding an additional nanoparticulate material with higher-frequency harmonic resonances to the hybrid films.

Determining the impact of gold nanoparticles on amyloid aggregation with 2D IR spectroscopy.

As nanomaterials become more prevalent in both industry and medicine, it is crucial to fully understand their health risks. One area of concern is the interaction of nanoparticles with proteins, including their ability to modulate the uncontrolled aggregation of amyloid proteins associated with diseases, such as Alzheimer's disease and type II diabetes, and potentially extend the lifetime of cytotoxic soluble oligomers. This work demonstrates that two-dimensional infrared spectroscopy and CO isotope labeling can be used to follow the aggregation of human islet amyloid polypeptide (hIAPP) in the presence of gold nanoparticles (AuNPs) with single-residue structural resolution.

Surface plasmon mediated harmonically resonant effects on third harmonic generation from Au and CuS nanoparticle films.

A growing class of nonlinear materials employ the localized surface plasmonic resonance (LSPR) of nanoparticles to enhance harmonic generation. Material systems containing harmonically coupled metallic and semiconductor plasmonic nanoparticles have been shown to further increase performance. Here, we explore the effect of dual plasmonic interactions in bilayer CuS and Au nanoparticle films on third harmonic generation (THG).

pH-Responsive Copolymer Films Prepared by Surface-Initiated Polymerization and Simple Modification.

We report the preparation of pH-responsive, ester/carboxylic acid random copolymer films via simple modification of poly(norbornene diacyl chloride) (pNBDAC), prepared via surface-initiated ring-opening metathesis polymerization, with mixtures of water and ethanol to form carboxylic acid and ethyl ester side groups. The pNBDAC film serves as a compositionally versatile platform to controllably obtain copolymers with multiple functionalities. In modifying the pNBDAC to form the copolymer film, ethanol exhibits a significantly higher reactivity with acyl chloride groups within the film than does water.

Analysis of regulatory guidance on antidrug antibody testing for therapeutic protein products.

Therapeutic proteins have the potential to induce unwanted immune responses. The potential impact of immunogenicity on pharmacokinetics, pharmacodynamics, safety and efficacy are well established. Here, we analyze key aspects of current US FDA and EMA guidelines on the development and validation of antidrug antibody assays.

A generic method for the detection of polyethylene glycol specific IgG and IgM antibodies in human serum.

Detection of anti-drug antibodies is a critical step in the development of large molecule biopharmaceuticals. In the case of multicomponent/multifunctional molecules, such as fusion proteins and protein conjugates such as covalent polyethylene glycol (PEG)~protein conjugates, it is useful to further characterize anti-drug antibody (ADA) binding to key domains of the drug. The detection of anti-PEG antibodies poses special challenges that if overlooked can result in underreporting antibody responses.

Tuning HS Release by Controlling Mobility in a Micelle Core.

Drug delivery from polymer micelles has been widely studied, but methods to precisely tune rates of drug release from micelles are limited. Here, the mobility of hydrophobic micelle cores was varied to tune the rate at which a covalently bound drug was released. This concept was applied to cysteine-triggered release of hydrogen sulfide (HS), a signaling gas with therapeutic potential.

Ligand cleavage enables formation of 1,2-ethanedithiol capped colloidal quantum dot solids.

Colloidal quantum dots have garnered significant interest in optoelectronics, particularly in quantum dot solar cells (QDSCs). Here we report QDSCs fabricated using a ligand that is modified, following film formation, such that it becomes an efficient hole transport layer. The ligand, O-((9H-fluoren-9-yl)methyl) S-(2-mercaptoethyl) carbonothioate (FMT), contains the surface ligand 1,2-ethanedithiol (EDT) protected at one end using fluorenylmethyloxycarbonyl (Fmoc).

4-Piperidin-4-ylidenemethyl-benzamides as δ-opioid receptor agonists for CNS indications: identifying clinical candidates.

A series of 4-piperidin-4-ylidenemethyl-benzamide δ-opioid receptor agonists is described with an emphasis on balancing the potency, subtype selectivity and in vitro ADME and safety properties. The three sites impacting SAR are substitutions on the aryl group (R(1)), the piperidine nitrogen (R(2)), and the amide (R(3)). Each region contributes to the balance of properties for δ opioid activity and a desirable CNS profile, and two clinical candidates (20 and 24) were advanced.

Preclinical profile of a novel metabotropic glutamate receptor 5 positive allosteric modulator.

Recent reports have indicated that patients with schizophrenia have a profound hypo-functionality of glutamatergic signaling pathways. Positive allosteric modulation of mGlu(5) receptor has been postulated to augment NMDA function and thereby alleviate the glutamatergic hypo-function observed in schizophrenic patients. Here we report the in vitro and in vivo characterization of CPPZ (1-(4-(2-chloro-4-fluorophenyl)piperazin-1-yl)-2-(pyridin-4-ylmethoxy)ethanone), a structurally novel positive allosteric modulator selective for mGlu(5) receptor.

Discovery of novel positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5).

Novel in vitro mGlu(5) positive allosteric modulators with good potency, solubility, and low lipophilicity are described. Compounds were identified which did not rely on the phenylacetylene and carbonyl functionalities previously observed to be required for in vitro activity. Investigation of the allosteric binding requirements of a series of dihydroquinolinone analogs led to phenylacetylene azachromanone 4 (EC(50) 11.

4-aryl piperazine and piperidine amides as novel mGluR5 positive allosteric modulators.

Positive allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) is regarded as a potential novel treatment for schizophrenic patients. Herein we report the synthesis and SAR of 4-aryl piperazine and piperidine amides as potent mGluR5 positive allosteric modulators (PAMs). Several analogs have excellent activity and desired drug-like properties.

Absence of direct effects on the dopamine D2 receptor by mGluR2/3-selective receptor agonists LY 354,740 and LY 379,268.

We previously reported the absence of high-affinity binding of the group II metabotropic glutamate receptor agonists LY 354,740 and LY 379,268 to the D2L dopamine receptor. A rebuttal to our findings has since been reported (see Introduction section); this study represents our response. Analysis by LCMS of LY 354,740 and LY 379,268 used in this study revealed the correct molecular mass for these compounds.

Discovery of mu-opioid selective ligands derived from 1-aminotetralin scaffolds made via metal-catalyzed ring-opening reactions.

A series of 1-aminotetralin scaffolds was synthesized via metal-catalyzed ring-opening reactions of heterobicyclic alkenes. Small libraries of amides and amines were made using the amino group of each scaffold as a handle. Screening of these libraries against human opioid receptors led to the identification of (S)-(S)-5.