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1.
Nano Lett ; 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38620021

ABSTRACT

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. Here we report the first observation of enhanced cascaded fourth- and fifth-harmonic generation in Al/Au/CuS driven by coupled LSPRs at the fundamental (1050 nm), second harmonic (525 nm), and third harmonic (350 nm) of the pump frequency. An analytical model based on incoherent dipole-dipole interactions among plasmonic nanoparticles accounts for the observed enhancements. The results suggest a novel design for efficiently generating higher harmonics in resonant plasmonic structures by means of multiple sum-frequency cascades.

2.
J Chem Phys ; 158(9): 091101, 2023 Mar 07.
Article in English | MEDLINE | ID: mdl-36889961

ABSTRACT

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 13C18O 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. 60 nm AuNPs were found to inhibit hIAPP, tripling the aggregation time. Furthermore, calculating the actual transition dipole strength of the backbone amide I' mode reveals that hIAPP forms a more ordered aggregate structure in the presence of AuNPs. Ultimately, such studies can provide insight into how mechanisms of amyloid aggregation are altered in the presence of nanoparticles, furthering our understanding of protein-nanoparticle interactions.


Subject(s)
Diabetes Mellitus, Type 2 , Metal Nanoparticles , Humans , Gold , Diabetes Mellitus, Type 2/metabolism , Islet Amyloid Polypeptide/chemistry , Amyloidogenic Proteins , Amyloid/chemistry , Spectrophotometry, Infrared
3.
Langmuir ; 36(3): 715-722, 2020 Jan 28.
Article in English | MEDLINE | ID: mdl-31917924

ABSTRACT

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. The magnitude and range of the pH-responsive performance are highly dependent on the carboxylic acid content in the copolymer films, which demonstrates the effect of film hydrophilicity on the pH-responsive switching of ionic barrier properties. The resistance of the film against ion transfer can be decreased by a factor of 104 through pH change, demonstrating pH-induced switching from hydrophobic and insulating to swollen and ion-permeable films. The interactions of the copolymer films with water at different pH values were also explored. When the copolymer contains 34% carboxylic acids, a 4× greater film thickness is obtained in high pH solution than in low pH solution due to ionically driven water swelling. The reversibility of the pH-responsive performance of these copolymer films is high based on measurements using quartz crystal microbalance with dissipation (QCM-D).

4.
Synapse ; 67(3): 135-44, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23150216

ABSTRACT

The positive allosteric modulator (PAM) binding site for metabotropic glutamate receptor subtype 5 (mGlu(5)) lacks a readily available radio-labeled tracer fordetailed structure-activity studies. This communication describes a selective mGlu(5) compound, 7-methyl-2-(4-(pyridin-2-yloxy)benzyl)-5-(pyridin-3-yl)isoindolin-1-one (PBPyl) that binds with high affinity to human mGlu(5) and exhibits functional PAM activity. Analysis of PBPyl by FLIPR revealed an EC(50) of 87 nM with an 89% effect in transfected HEK293 cells and an EC(50) of 81 nM with a 42% effect in rat primary neurons. PBPyl exhibited 5-fold higher functional selectivity for mGlu(5) in a full mGlu receptor panel. Unlabeled PBPyl was tested for specific binding using a liquid chromatography mass spectrometry (LC/MS/MS)-based filtration binding assay and exhibited 40% specific binding in recombinant membranes, a value higher than any candidate compound tested. In competition binding studies with [(3)H]MPEP, the mGlu(5) receptor negative allosteric modulator (NAM), PBPyl exhibited a k(i) value of 34 nM. PBPyl also displaced [(3)H]ABP688, a mGluR(5) receptor NAM, in tissue sections from mouse and rat brain using autoradiography. Areas of specific binding included the frontal cortex, striatum and nucleus accumbens. PBPyl was radiolabeled to a specific activity of 15 Ci/mmol and tested for specific binding in a filter plate format. In recombinant mGlu(5b) membranes, [(3)H] PBPyl exhibited saturable binding with a K(d) value of 18.6 nM. In competition binding experiments, [(3)H] PBPyl was displaced by high affinity mGlu(5) positive and negative modulators. Further tests showed that PBPyl displays less than optimal characteristics as an in vivo tool, including a high volume of distribution and ClogP, making it more suitable as an in vitro compound. However, as a first report of direct binding of an mGlu(5) receptor PAM, this study offers value toward the development of novel PET imaging agents for this important therapeutic target.


Subject(s)
Isoindoles/pharmacology , Pyridines/pharmacology , Receptors, Metabotropic Glutamate/metabolism , Allosteric Regulation , Allosteric Site , Animals , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/pharmacology , HEK293 Cells , Humans , Isoindoles/chemistry , Isoindoles/metabolism , Male , Mass Spectrometry , Mice , Oximes/pharmacology , Protein Binding , Pyridines/chemistry , Pyridines/metabolism , Radioactive Tracers , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/antagonists & inhibitors
5.
Bioorg Med Chem Lett ; 22(2): 1174-8, 2012 Jan 15.
Article in English | MEDLINE | ID: mdl-22197137

ABSTRACT

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.


Subject(s)
Benzamides/pharmacology , Central Nervous System/drug effects , Piperidines/pharmacology , Receptors, Opioid, delta/agonists , Benzamides/chemistry , Central Nervous System/metabolism , Dose-Response Relationship, Drug , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , HEK293 Cells , Humans , Molecular Structure , Piperidines/chemistry , Receptors, Opioid, delta/metabolism , Stereoisomerism , Structure-Activity Relationship
6.
Synapse ; 65(1): 64-8, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20506301

ABSTRACT

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. Both LY 354,740 and LY 379,268 exhibited potent agonist activity for mGluR2 in the ³5S-GTPγS assay. Functionally, neither compound displayed antagonist activity in the GTPγS assay with recombinant D2. At concentrations up to 10 µM, both compounds failed to displace [³H]-raclopride, [³H]-PHNO, or [³H]-domperidone in filter-binding assays under isotonic (120 mM NaCl or N-methyl glucamine) or low-ionic strength (no NaCl or N-methyl glucamine) conditions. Some displacement of [³H]-domperidone (20-40%) was observed at 30 µM of LY 354,740 under low-ionic strength and under isotonic conditions in the absence of NaCl. No displacement of [³H]-domperidone was detected in a two site model at lower (<100 nM) concentrations of either compound. Moreover, no D2 activity was observed for LY 354,740 or LY 379,268 in the CellKey™ (cellular dielectric spectroscopy) assay. In this communication, we discuss the possible reasons for differences in our study and the previously published work and implications of these studies for mechanisms of antipsychotic action.


Subject(s)
Amino Acids/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bridged Bicyclo Compounds/pharmacology , Receptors, Dopamine D2/metabolism , Receptors, Metabotropic Glutamate/agonists , Animals , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Domperidone/pharmacology , Excitatory Amino Acid Agonists/pharmacology , Mass Spectrometry , Raclopride/pharmacology , Radioligand Assay
7.
Bioorg Med Chem Lett ; 21(5): 1402-6, 2011 Mar 01.
Article in English | MEDLINE | ID: mdl-21295468

ABSTRACT

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) 11.5 nM). Because of risks associated with potential metabolic and toxicological liabilities of the phenylacetylene, this moiety was successfully replaced with a phenoxymethyl group (27; EC(50) 156.3 nM). Derivation of a second-generation of mGlu(5) PAMs lacking a ketone carbonyl resulted in azaindoline (33), azabenzimidazole (36), and N-methyl 8-azaoxazine (39) phenylacetylenes. By scoping nitrogen substituents and phenylacetylene replacements in 39, we identified phenoxymethyl 8-azaoxazine 47 (EC(50) 50.1 nM) as a potent and soluble mGlu(5) PAM devoid of both undesirable phenylacetylene and carbonyl functionalities.


Subject(s)
Drug Design , Receptors, Metabotropic Glutamate/metabolism , Allosteric Regulation , Inhibitory Concentration 50 , Receptor, Metabotropic Glutamate 5
8.
Bioorg Med Chem Lett ; 20(24): 7381-4, 2010 Dec 15.
Article in English | MEDLINE | ID: mdl-21067920

ABSTRACT

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. Compound 2b was further characterized as a PAM using several in vitro experiments, and produced robust activity in several preclinical animal models.


Subject(s)
Amides/chemistry , Piperazines/chemistry , Piperidines/chemistry , Receptors, Metabotropic Glutamate/chemistry , Allosteric Regulation , Amides/chemical synthesis , Amides/therapeutic use , Humans , Microsomes, Liver/metabolism , Piperazine , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/metabolism , Schizophrenia/drug therapy , Structure-Activity Relationship
9.
Bioorg Med Chem Lett ; 19(4): 1228-32, 2009 Feb 15.
Article in English | MEDLINE | ID: mdl-19168350

ABSTRACT

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)-5.2a as a high-affinity selective mu ligand (IC(50)mu=5 nM, kappa=707 nM, delta=3,795 nM) displaying mu-agonist/antagonist properties due to its partial agonism (EC(50)=2.6 microM; E(max)=18%).


Subject(s)
Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/pharmacology , Combinatorial Chemistry Techniques , Rhodium/chemistry , Analgesics, Opioid/chemistry , Catalysis , Humans , Ligands , Molecular Structure , Stereoisomerism
10.
J Immunol Methods ; 474: 112669, 2019 11.
Article in English | MEDLINE | ID: mdl-31614128

ABSTRACT

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. Here we describe the development and characterization of a novel ELISA to detect anti-PEG antibodies that provides a more complete interpretation of anti-PEG than other published methods. Being specific to the PEG moiety alone, this method is intended to detect anti-PEG antibodies independent of the protein to which PEG is conjugated. Based upon early indications that our assay could detect anti-PEG antibodies at a surprisingly high frequency in the general population, our emphasis throughout method development and validation was to ensure that non-specific signals and unintended interactions were not falsely contributing to detection of anti-PEG antibodies. Techniques, including orthogonal methods used to ensure that this ELISA detected antibodies specific to PEG included competition, immunodepletion, immunoprecipitation/western blot and an Octet kinetic binding analysis. The validated ELISA can detect 100 ng/mL of an anti-PEG IgG positive control and 800 ng/mL of an anti-PEG IgM positive control in the presence of 7.5 µg/mL of the PEGylated therapeutic (MW 64 kDa). The intra-assay percent co-efficient of variation (CV) and inter-assay CV of the low positive control samples in the screening method were 4.1 to 7.2% and 16.7 to 17.7%, respectively. Additional assay performance parameters that were validated are also described. When the validated assay was applied to a population of 200 healthy blood donors with no known exposure to biopharmaceutical PEG conjugates it indicated a pre-existing anti-PEG antibody prevalence of 97.5%. We suggest this surprising result is a consequence of exposure to PEG additives in everyday products, such as cosmetics, processed foods and over-the-counter (OTC) pharmaceuticals.


Subject(s)
Antigens/immunology , Enzyme-Linked Immunosorbent Assay , Immunoglobulin G/blood , Immunoglobulin M/blood , Polyethylene Glycols , Antigens/metabolism , Binding Sites, Antibody , Humans , Kinetics , Polyethylene Glycols/metabolism , Protein Binding , Reproducibility of Results , Surface-Active Agents/chemistry
11.
Bioanalysis ; 11(24): 2283-2296, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31845602

ABSTRACT

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. Although FDA and EMA guidance documents are in harmony on most points, EMA allows greater leeway for scientific judgement, while FDA recommends specific approaches that may not be appropriate in some situations. Many white papers suggest approaches different from the guidance documents, however, these can conflict with each other and are themselves only scientifically valid in certain situations. Here, we indicate when alternatives to guidance may be needed and what those approaches might be.


Subject(s)
Antibodies/therapeutic use , Proteins/therapeutic use , United States Food and Drug Administration/standards , Antibodies/pharmacology , Humans , Proteins/pharmacology , United States
12.
Macromolecules ; 52(3): 1104-1111, 2019 Feb 12.
Article in English | MEDLINE | ID: mdl-31354172

ABSTRACT

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 (H2S), a signaling gas with therapeutic potential. In this system, thiol-triggered H2S donor molecules were covalently linked to the hydrophobic blocks of self-assembled polymer amphiphiles. Because release of H2S is triggered by cysteine, diffusion of cysteine into the hydrophobic micelle core was hypothesized to control the rate of release. We confirmed this hypothesis by carrying out release experiments from H2S-releasing micelles in varying compositions of EtOH/H2O. Higher EtOH concentrations caused the micelles to swell, facilitating diffusion in and out of their hydrophobic cores and leading to faster H2S release from the micelles. To achieve a similar effect without addition of organic solvent, we prepared micelles with varying core mobility via incorporation of a plasticizing co-monomer in the core-forming block. The glass transition temperature (Tg) of the core block could therefore be precisely varied by changing the amount of the plasticizing co-monomer in the polymer. In aqueous solution under identical conditions, the release rate of H2S varied over 20-fold (t½ = 0.18 - 4.2 h), with the lowest Tg hydrophobic block resulting in the fastest H2S release. This method of modulating release kinetics from polymer micelles by tuning core mobility may be applicable to many types of physically encapsulated and covalently linked small molecules in a variety of drug delivery systems.

13.
Nanoscale ; 11(22): 10774-10781, 2019 Jun 06.
Article in English | MEDLINE | ID: mdl-31134264

ABSTRACT

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). The strategy enables deprotection following colloidal deposition, producing films containing quantum dots whose surfaces are more thoroughly covered with the remaining EDT molecules. To compare fabrication methods, we deposited CQDs onto the active layer: in one case, the traditional EDT-PbS/EDT-PbS is used, while in the other EDT-PbS/FMT-PbS is used. The devices based on the new EDT/FMT match the PCE values of EDT/EDT controls, and maintain a higher PCE over an 18 day storage interval, a finding we attribute to an increased thiol coverage using the FMT protocol.

14.
Eur J Pharmacol ; 659(2-3): 146-54, 2011 Jun 01.
Article in English | MEDLINE | ID: mdl-21335002

ABSTRACT

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. In HEK293 cells stably over-expressing human mGlu(5) receptor, CPPZ potentiates the intracellular calcium response elicited by a suboptimal concentration of the endogenous agonist glutamate. CPPZ does not have any intrinsic agonist activity and behaves functionally as a positive allosteric modulator. This is further supported by binding data, which demonstrate that CPPZ is able to displace the negative allosteric modulator MPEP but does not compete with the orthosteric ligand quisqualic acid. Instead, CPPZ enhances the binding of the orthosteric ligand. In native preparations, CPPZ potentiates calcium flux in rat cortical neurons stimulated with the group I agonist dihydroxyphenylglycine (DHPG). In addition, CPPZ modulates long-term potentiation in rat hippocampal slices, a process known to be NMDA dependent. In vivo, CPPZ reverses hyper locomotion triggered by the NMDA open channel blocker MK801 in CD1 mice. CPPZ was also able to reduce rat conditioned avoidance responding to electric shock. Both in vitro and in vivo data demonstrate that this novel compound acts as an mGlu(5) receptor positive allosteric modulator, which modulates NMDA dependent responses and suggests that the enhancement of mGlu(5) receptor activity may prove useful in the treatment of schizophrenia.


Subject(s)
Antipsychotic Agents/pharmacology , Piperazines/pharmacology , Pyridines/pharmacology , Receptors, Metabotropic Glutamate/metabolism , Allosteric Regulation/drug effects , Animals , Antipsychotic Agents/metabolism , Antipsychotic Agents/therapeutic use , Avoidance Learning/drug effects , Cerebral Cortex/cytology , Conditioning, Psychological/drug effects , Dizocilpine Maleate/antagonists & inhibitors , Dizocilpine Maleate/pharmacology , Drug Evaluation, Preclinical , Gene Expression Regulation/drug effects , Guinea Pigs , HEK293 Cells , Hippocampus/cytology , Hippocampus/physiology , Humans , Hyperkinesis/chemically induced , Hyperkinesis/drug therapy , Long-Term Potentiation/drug effects , Male , Mice , Neurons/drug effects , Neurons/metabolism , Piperazine , Piperazines/metabolism , Piperazines/therapeutic use , Pyridines/metabolism , Pyridines/therapeutic use , Rats , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/chemistry , Receptors, N-Methyl-D-Aspartate/metabolism
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