As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu2/3) receptors, we have incorporated substitution at the C3 and C4 positions of the ...(1S,2R,5R,6R)-2-amino-bicyclo3.1.0hexane-2,6-dicarboxylic acid scaffold to generate mGlu2/3 antagonists. Exploration of this structure–activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-(3,4-difluorophenyl)sulfanylmethyl-4-hydroxy-bicyclo3.1.0hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu2/3 antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu2) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu2 receptor protein. The resulting cocrystal structure revealed the specific ligand–protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu2 antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu2 IC50 value.
In this paper, we describe the design considerations and implementation of a smart toy system, a technology for supporting the automatic recording and analysis for detecting developmental delays ...recognition when children play using the smart toy. To achieve this goal, we take advantage of the current commercial sensor features (reliability, low consumption, easy integration, etc.) to develop a series of sensor-based low-cost devices. Specifically, our prototype system consists of a tower of cubes augmented with wireless sensing capabilities and a mobile computing platform that collect the information sent from the cubes allowing the later analysis by childhood development professionals in order to verify a normal behaviour or to detect a potential disorder. This paper presents the requirements of the toy and discusses our choices in toy design, technology used, selected sensors, process to gather data from the sensors and generate information that will help in the decision-making and communication of the information to the collector system. In addition, we also describe the play activities the system supports.
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Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment ...of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo3.1.0hexane glutamic acid analogs as orthosteric (glutamate site) mGlu2/3 receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu2 IC50 46±14.2nM, hmGlu3 IC50=46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu2/3 receptors both in vitro and in vivo.
A practical and scalable method for the synthesis of 2-(dimethylamino)-6-methylpyridin-4-ol is described. Despite its structural simplicity, the synthesis and isolation of this molecule in useful ...yields has proven to be challenging. A hybrid-flow (flow–batch–flow) mode approach was designed to circumvent issues associated with the safety and technical limitations of some of the steps in the process. The synthesis was successfully implemented to generate multigram quantities of a key intermediate for a drug candidate.
Chrysopids are potential biological control agents of arthropods. Chysopid larvae prey on eggs, nymphs, larvae and pupa of coffee (Coffea arabica L.) pests. The objective of this study was to ...determine a sampling unit for Chrysoperla spp. eggs in coffee plants. We evaluated commercial fields of C. arabica cv. Catuaí 144 and determined the number of Chrysoperla spp. eggs on a pair of leaves located on a branch with the greatest leaf frequency. The third pair of leaves from the middle part of plant canopy was selected as the best location to sampling Chrysoperla spp. Sample unit validation showed a positive and significant relationship between the total number of eggs on the plant and the number of eggs on the 3
rd
to 5
th
pairs of coffee leaves. The selected sampling unit reduced the time required to sample Chrysoperla spp. by 71.7%. Sampling eggs of Chrysoperla spp. should focus on the abaxial surface of 3
rd
pair of coffee leaves.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Some evidence shows that Cu-based fungicides used on vines increase the levels of copper in soil and sediments. The rainfall induced foliar wash-off is the most complex pathway of contaminants in the ...environment. Since the Cu wash-off occurs during rain episodes, Cu can be transported in streams along considerable distances as particulate forms. The colloidal properties of Cu suspended in runoff are related to its mobility in the environment. Asymmetrical-flow field-flow fractionation (AF4) performs colloid separation based on hydrodynamic properties and can contribute as a useful tool to understand the environmental fate of colloidal contaminants. In this work, we studied the Cu-bearing micro- and nanoparticles (NPs) in throughfall samples containing fungicide residues of vines previously sprayed with copper oxychloride. Suspended particles in the throughfall were characterized by Dynamic light scattering (DLS) and AF4 coupled to multi-angle laser light scattering and inductively coupled plasma mass spectrometry (AF4-MALLS-ICP-MS). Then, single-particle ICP-MS analysis (SP-ICP-MS) was performed to evaluate the presence of Cu NPs. AF4 allowed particle fractionation and detection in throughfall waters coupled AF4-MALLS-ICP-MS demonstrating that Cu was bound to a well-defined fraction of small particles clearly separated from a broad size distribution of organic colloids that did not contain Cu. SP-ICP-MS supported the evidence that throughfall contained Cu bound to organo-mineral particles of much smaller size than the powder formulation sprayed on vines, which favors their mobility in natural waters.
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•Foliar wash-off from treated vines was analyzed with AF4-MALLS-ICP-MS and SP-ICP-MS.•AF4-MALLS and DLS gave similar estimations of the particle size distribution.•Particle sizes ranging from 50 to 350nm do not carry any Cu.•Most Cu was attached to organo-mineral nanoparticles with sizes between 25 and 152nm.
Herein we report a summary of the synthetic development of LY3202626 from the initial discovery route to a final route that was scaled to make 150 kg. Key developments include the use of a 3 + 2 ...cyclization to set the cis ring junction of the formed isoxazoline, a one-pot thiazine formation, and three different ways to install the aniline: (1) Cu-catalyzed azide coupling and reduction, (2) nitration and reduction, and (3) Buchwald coupling with acetamide.
The dynamic NMR analysis of
2, a subunit of a new class of cyclic-dependent kinase inhibitors, reveals that the compound exists as two conformational isomers,
Z and
E, in acetone, as a consequence of ...the restricted rotation about the imidazopyridine–carbonyl bond. The less hindered
Z-rotamer is the most abundant conformer (85:15
Z/
E at 233
K) and the free energy of activation of the interconversion is 13.2
kcal
mol
−1. The rotamer ratio and the interconversion barrier are similar in other solvents, such as CD
3OD and CDCl
3.
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The protein kinase family represents an enormous opportunity for drug development. However, the current limitation in structural
diversity of kinase inhibitors has complicated efforts to identify ...effective treatments of diseases that involve protein kinase
signaling pathways. We have identified a new structural class of protein serine/threonine kinase inhibitors comprising an
aminoimidazo1,2- a pyridine nucleus. In this report, we describe the first successful use of this class of aza-heterocycles to generate potent
inhibitors of cyclin-dependent kinases that compete with ATP for binding to a catalytic subunit of the protein. Co-crystal
structures of CDK2 in complex with lead compounds reveal a unique mode of binding. Using this knowledge, a structure-based
design approach directed this chemical scaffold toward generating potent and selective CDK2 inhibitors, which selectively
inhibited the CDK2-dependent phosphorylation of Rb and induced caspase-3-dependent apoptosis in HCT 116 tumor cells. The discovery
of this new class of ATP-site-directed protein kinase inhibitors, aminoimidazo1,2- a pyridines, provides the basis for a new medicinal chemistry tool to be used in the search for effective treatments of cancer
and other diseases that involve protein kinase signaling pathways.
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