Identification of Novel Dopamine D2 Receptor Ligands—A Combined In Silico/In Vitro Approach

Diseases of the central nervous system are an alarming global problem showing an increasing prevalence. Dopamine receptor D₂ (D₂R) has been shown to be involved in central nervous system diseases. While different D₂R-targeting drugs have been approved by the FDA, they all suffer from major drawbacks due to promiscuous receptor activity leading to adverse effects. Increasing the number of potential D₂R-targeting drug candidates bears the possibility of discovering molecules with less severe side-effect profiles. In dire need of novel D₂R ligands for drug development, combined in silico/in vitro approaches have been shown to be efficient strategies. In this study, in silico pharmacophore models were generated utilizing both ligand- and structure-based approaches. Subsequently, different databases were screened for novel D₂R ligands. Selected virtual hits were investigated in vitro, quantifying their binding affinity towards D₂R. This workflow successfully identified six novel D₂R ligands exerting micro- to nanomolar (most active compound K_I = 4.1 nM) activities. Thus, the four pharmacophore models showed prospective true-positive hit rates in between 4.5% and 12%. The developed workflow and identified ligands could aid in developing novel drug candidates for D₂R-associated pathologies.     

Synthesis of 7,8‐Dihydrothieno[3′,2′:4,5]pyrrolo[1,2‐a]pyrazin‐5(6H)‐ones Using a Modification of Four‐Component Ugi Reaction

We describe an efficient synthesis of novel 7,8‐dihydrothieno [3′,2′:4,5]pyrrolo[1,2‐a]pyrazin‐5(6H)‐one heterocyclic structures. The target compounds were prepared by a novel modification of four‐component Ugi reaction of heterocyclic bifunctional keto acids, isonitriles, and amines. We demonstrate the usefulness and versatility of the developed approach, which is amenable to production of combinatorial libraries.     

Comparative Solution Synthesis of Mn Doped (Na,K)NbO3 Thin Films

(K_0.5Na_0.5)NbO₃ (KNN) is a promising lead-free alternative for ferroelectric thin films such as Pb(Zr,Ti)O₃. One main drawback is its high leakage current density at high electric fields, which has been previously linked to alkali non-stoichiometry. This paper compares three acetate-based chemical solution synthesis and deposition methods for 0.5 mol % Mn-doped KNN film fabrication, using lower crystallization temperature processes in comparison to the sintering temperatures necessary for fabrication of KNN ceramics. This paper shows the crucial role of the A site homogenization step during solution synthesis in preserving alkali chemical homogeneity of Mn doped KNN films. Chemically homogeneous films show a uniform grain size of 80 nm and a leakage current density under 2.8×10⁻⁸ A cm⁻² up to electric fields as high as 600 kV cm⁻¹, which is the highest breakdown strength reported for KNN thin films. Solution synthesis involving two-step pyrolysis resulted in films with dense, columnar microstructures, which are interesting for orientation control and enhancement of piezoelectric properties. This study reports detailed solution synthesis and deposition processes with good dielectric, ferroelectric and breakdown field properties. An optimized fabrication method that should couple low leakage current density with dense and oriented microstructures is proposed.     

Cold Atmospheric Pressure Plasma Can Induce Adaptive Response in Pea Seeds

Plasma Chemistry and Plasma Processing - This study investigated the effect of cold atmospheric pressure air plasma pre-treatment on pea (Pisum sativum L.) seeds. The aim of our study was to verify...     

Effect of hypercrosslinking conditions on pore size distribution and efficiency of monolithic stationary phases

Three dihalogenic solvents differing in the length of alkyl chain (1,2‐dichloroethane, 1,4‐dichlorobutane, and 1,6‐dichlorohexane) with three Friedel–Crafts alkylation catalysts varying in reactivity (AlCl₃, FeCl₃, and SnCl₄) have been used to prepare hypercrosslinked poly(styrene‐co‐vinylbenzyl chloride‐co‐divinylbenzene) columns. Hydrodynamic characteristics as well as column efficiency and mass transfer resistance were tuned by the combination of swelling solvent and alkylation reaction catalyst in the modification mixture. The column swelled in 1,6‐dichlorohexane and hypercrosslinked in the presence of AlCl₃ provided the highest column efficiency and enabled fast isocratic separations of small molecules in a RP mode. To uncover factors controlling the efficiency of hypercrosslinked monolithic columns, we have studied pore volume distribution of prepared columns. We found that column efficiency increases with the higher pore volume of pores smaller than 2 nm.     

Sparsity optimized high order finite element functions for H(div) on simplices

This paper deals with conforming high-order finite element discretizations of the vector-valued function space H(Div) in 2 and 3 dimensions. A new set of hierarchic basis functions on simplices with the following two main properties is introduced. When working with an affine, simplicial triangulation, first, the divergence of the basis functions is L ₂-orthogonal, and secondly, the L ₂-inner product of the interior basis functions is sparse with respect to the polynomial degree p. The construction relies on a tensor-product based construction with properly weighted Jacobi polynomials as well as an explicit splitting of the higher-order basis functions into solenoidal and non-solenoidal ones. The basis is suited for fast assembling strategies. The general proof of the sparsity result is done by the assistance of computer algebra software tools. Several numerical experiments document the proved sparsity patterns and practically achieved condition numbers for the parameter-dependent Div - Div problem. Even on curved elements a tremendous improvement in condition numbers is observed. The precomputed mass and stiffness matrix entries in general form are available online.     

The Clever Use of Pressure in Column Liquid Chromatography

The pressure limits of a liquid chromatographic instrument can be maxed out by running the separation at the highest possible flow rate. This approach reduces analysis time but it does not save solvent and the separation will be poorer due to the properties of the van Deemter curve. Thus, it is better to use a shorter column with smaller particle size because both analysis time and solvent consumption will decrease while the resolution will remain constant. This paper shows how to utilize the pressure which is offered by a certain LC instrument in a clever way. It explains the algebraic background and illustrates the validity of the approach with two analytical problems, namely the separation of seven doping agents and of six drugs.     

Experiments on the synthesis of carotenoid glycosides

Isozeaxanthin was treated with trifluoroacetic acid and tetra-O-benzoyl-1-thio-β-d-glucose to afford β,β-carotene-4,4′-bisthioglucoside isomers in good yields. The deprotected compounds are mimetics of naturally occurring thermoxanthins and can show favourable effects against oxidation stress.     

An extended Stickelberger ideal of the compositum of a bicyclic field and an imaginary quadratic field

We consider certain extension of the Stickelberger ideal of the compositum of a bicyclic field and a quadratic imaginary field, obtained by adding new annihilators to the Stickelberger ideal. We compute the index of this extension, from which we get some divisibility properties for the relative class number of the compositum.     

Use of the Kinetic Plot Method to Compare the Efficiency and Resolution of Liquid-Phase Separation Techniques Based on Different Driving Forces

JPC – Journal of Planar Chromatography – Modern TLC - Much effort has been devoted to improving the capability of separation techniques. The lower the separation volume and the higher...