Pathophysiological Role and Medicinal Chemistry of A2A Adenosine Receptor Antagonists in Alzheimer’s Disease

The A_2A adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. It is involved in the regulation of several pathophysiological conditions in both the central nervous system and periphery. In the brain, its localization at pre- and postsynaptic level in striatum, cortex, hippocampus and its effects on glutamate release, microglia and astrocyte activation account for a crucial role in neurodegenerative diseases, including Alzheimer’s disease (AD). This ailment is considered the main form of dementia and is expected to exponentially increase in coming years. The pathological tracts of AD include amyloid peptide-β extracellular accumulation and tau hyperphosphorylation, causing neuronal cell death, cognitive deficit, and memory loss. Interestingly, in vitro and in vivo studies have demonstrated that A_2A adenosine receptor antagonists may counteract each of these clinical signs, representing an important new strategy to fight a disease for which unfortunately only symptomatic drugs are available. This review offers a brief overview of the biological effects mediated by A_2A adenosine receptors in AD animal and human studies and reports the state of the art of A_2A adenosine receptor antagonists currently in clinical trials. As an original approach, it focuses on the crucial role of pharmacokinetics and ability to pass the blood–brain barrier in the discovery of new agents for treating CNS disorders. Considering that A_2A receptor antagonist istradefylline is already commercially available for Parkinson’s disease treatment, if the proof of concept of these ligands in AD is confirmed and reinforced, it will be easier to offer a new hope for AD patients.     

Modelling Protein Plasticity: The Example of Frataxin and Its Variants

Frataxin (FXN) is a protein involved in storage and delivery of iron in the mitochondria. Single-point mutations in the FXN gene lead to reduced production of functional frataxin, with the consequent dyshomeostasis of iron. FXN variants are at the basis of neurological impairment (the Friedreich’s ataxia) and several types of cancer. By using altruistic metadynamics in conjunction with the maximal constrained entropy principle, we estimate the change of free energy in the protein unfolding of frataxin and of some of its pathological mutants. The sampled configurations highlight differences between the wild-type and mutated sequences in the stability of the folded state. In partial agreement with thermodynamic experiments, where most of the analyzed variants are characterized by lower thermal stability compared to wild type, the D104G variant is found with a stability comparable to the wild-type sequence and a lower water-accessible surface area. These observations, obtained with the new approach we propose in our work, point to a functional switch, affected by single-point mutations, of frataxin from iron storage to iron release. The method is suitable to investigate wide structural changes in proteins in general, after a proper tuning of the chosen collective variable used to perform the transition.     

A Robust Protocol for Entropy Measurement in Mesoscopic Circuits

Previous measurements utilizing Maxwell relations to measure change in entropy, S, demonstrated remarkable accuracy in measuring the spin-1/2 entropy of electrons in a weakly coupled quantum dot. However, these previous measurements relied upon prior knowledge of the charge transition lineshape. This had the benefit of making the quantitative determination of entropy independent of scale factors in the measurement itself but at the cost of limiting the applicability of the approach to simple systems. To measure the entropy of more exotic mesoscopic systems, a more flexible analysis technique may be employed; however, doing so requires a precise calibration of the measurement. Here, we give details on the necessary improvements made to the original experimental approach and highlight some of the common challenges (along with strategies to overcome them) that other groups may face when attempting this type of measurement.     

Multilayer films composed of conductive poly(3‐hydroxybutyrate)/carbon nanotubes bionanocomposites and a photoresponsive conducting polymer

In order to develop new electronic devices, it is necessary to find innovative solutions to the eco‐sustainability problem of materials as substrates for circuits. We realized a photoresponsive device consisting of a semiconducting polymer film deposited onto optically semitransparent and conductive biodegradable poly(3‐hydroxybutyrate) (PHB)/carbon nanotube (CNT) substrates. The experiments indicated that the PHB‐CNT bionanocomposite substrate behaves as an optical window trapping electric charges produced by the photoexcitation of the semiconducting polymer. Such PHB‐CNT functional substrates are expected to be attractive for eco‐friendly electronics. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2014 , 52, 596–602     

Effect of steam on the structural and morphological stability of renewable poly(ether‐block‐amide)s

The effect of steam on chemical structure and mechanical properties of renewable poly(ether‐block‐amide)s (PEBAs) is investigated by different characterization techniques, i.e. FT‐IR, TGA, DSC, DMA, and BES. Steam sterilization is a mandatory process for materials used in medical applications. This process, employed during clinical practice and replicated in this study, affects polymer structure and morphology. Steam induces an increase of polyamide (PA) crystallinity in PEBAs with a majority of PA domains, due to the conformational transition from α‐helix to parallel and anti‐parallel β‐sheet, with stronger hydrogen bonding. In PEBAs with longer polyether (PE) blocks, steam induces an increase of random PA domains and the formation of a more extended hydrogen bonding network between ether and amide moieties of the two segments. As a consequence of these microdomain conformational variations, relevant changes occur in molecular relaxations as demonstrated by DMA and BES results. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2014 , 52, 409–418     

Tris(3,5‐dimethylpyrazolyl)methane‐Based Heterobimetallic Complexes that Contain Zn and CdTransition‐Metal Bonds: Synthesis,Structures, and Quantum Chemical Calculations

Reactions of the tris(3,5‐dimethylpyrazolyl)methanide amido complexes [M′{C(3,5‐Me₂pz)₃}{N(SiMe₃)₂}] (M′=Mg ( 1 a ), Zn ( 1 b ), Cd ( 1 c ); 3,5‐Me₂pz=3,5‐dimethylpyrazolyl) with two equivalents of the acidic Group 6 cyclopentadienyl (Cp) tricarbonyl hydrides [MCp(CO)₃H] (M=Cr ( 2 a ), Mo ( 2 b )) gave different types of heterobimetallic complex. In each case, two reactions took place, namely the conversion of the tris(3,5‐dimethylpyrazolyl)methanide ligand (Tpmd*) into the ‐methane derivative (Tpm*) and the reaction of the acidic hydride M?H bond with the M′?N(SiMe₃)₂ moiety. The latter produces HN(SiMe₃)₂ as a byproduct. The Group 2 representatives [Mg(Tpm*){MCp(CO)₃}₂(thf)] ( 3 a / b ) form isocarbonyl bridges between the magnesium and chromium/molybdenum centres, whereas direct metal–metal bonds are formed in the case of the ions [Zn(Tpm*){MCp(CO)₃}]⁺ ( 4 a / b ; [MCp(CO)₃]^? as the counteranion) and [Cd(Tpm*){MCp(CO)₃}(thf)]⁺ ( 5 a / b ; [Cd{MCp(CO)₃}₃]^? as the counteranion). Complexes 4 a and 5 a / b are the first complexes that contain Zn?Cr, Cd?Cr, and Cd?Mo bonds (bond lengths 251.6, 269.8, and 278.9 pm, respectively). Quantum chemical calculations on 4 a / b* (and also on 5 a / b* ) provide evidence for an interaction between the metal atoms.