The glycine receptor (GlyR) is a ligand-gated ion channel and a member of the cys-loop receptor family. Like other members of this family, the GlyR is a target for many drugs of abuse, including alcohol. While the effects of alcohol on these receptors have been well-characterized, the contribution of each receptor subtype to the overall physiological and behavioral effects of alcohol use are unclear. This is partially due to the limited pharmacology of the GlyR, which limits the ability to isolate GlyR function within a complex system. One method for identifying compounds that bind to and modulate a given target is phage display. This approach uses bacteriophage to screen a large number of peptide sequences for affinity at a given target. We developed a phage selection protocol to identify peptides that bind to the GlyR. These peptides were then tested for functional effects at the GlyR using two-electrode voltage clamp physiology. We identified several peptides that were able to modulate GlyR function. Peptide D12-116 showed specificity for the GlyR over two closely related γ-aminobutyric acid (GABA) channels. In addition, this method is easily adapted for the selection of peptides that bind to any cell-expressed target, increasing the utility of phage display in the neurobiology field. Another shortcoming in GlyR pharmacology is the lack of modulators with specificity for a single GlyR subtype. We next adjusted our selection protocol to search for peptides that can distinguish between the different Gly R α subtypes. We identified several promising lead peptides that show subtype preference. Finally, we found that trifluoroacetic acid (TFA), a common peptide contaminant, also modulates GlyR function. This finding has important implications for both previously reported peptide modulators and the pharmacology of several volatile anesthetics, for which TFA is the major metabolite / text

The most efficient homogeneous catalysts for hydroxylation of light alkanes utilize transition metals in superacid solvent and operate by tandem electrophilic C-H activation/metal-alkyl (M-R) functionalization. An emerging alternative strategy to transition metals is the use of high-oxidation state main-group metals (e.g. TlIII, PbIV, IIII) that hydroxylate light alkanes. This dissertation reports density-functional theory calculations that reveal the mechanisms, reactivity, and selectivity of TlIII promoted alkane C-H functionalization in trifluoroacetic acid and TlIII-dialkyl functionalization in water. Calculations reveal that TlIII oxidizes alkanes via a closed-shell C-H activation and M-R functionalization mechanism that is similar to transition-metal C-H functionalization mechanisms. Comparison of TlIII to similar transition metals reveals that while TlIII and transition metals can have similar activation barriers for C-H activation, TlIII M-R functionalization is significantly faster due to a highly polar Tl-C bond and large TlIII/TlI reduction potential. The combination of a moderate C-H activation barrier combined with a low M-R functionalization barrier is critical to the success for TlIII promoted alkane C-H oxidation. The proposed TlIII C-H activation/M-R functionalization mechanism also provides an explanation for ethane conversion to a mixture of ethyl trifluoroacetate and ethane-1,2-diyl bis(2,2,2-trifluoroacetate). The reactivity of TlIII contrasts the lack of alkane oxidation by HgII. The C-H activation transition state and frontier-orbital interactions provide a straightforward explanation for the higher reactivity of TlIII versus HgII. This frontier-orbital model also provides a rationale for why the electron-withdrawing group in EtTFA provides "protection" against overoxidation. Calculations also reveal that TlIII-dialkyl functionalization by inorganic TlIII in water occurs by alkyl group transfer to form a TlIII-monoalkyl complex that is rapidly functionalized.

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Ce travail de thèse a pour but de suivre le comportement du liant ionomère après vieillissement en condition réelle d'utilisation de la pile. Dans un premier temps, diverses techniques de caractérisation en phase solide ont été utilisées afin d'étudier le ionomère présent dans les électrodes. La majeure partie de ces techniques se sont avérées insatisfaisantes pour le suivi du vieillissement du ionomère. Seule l'analyse par diffraction rayon X (DRX) a mis en avant un changement d'organisation structurale du ionomère dans les électrodes. Par la suite, nous avons choisi de caractériser le ionomère en solution après extraction par l'eau. Préalablement, un protocole de quantification en 2 à 3 étapes, dans lequel intervient une quantification via le rapport signal-sur-bruit (S/N), a été mis en place afin de quantifier le Nafion® et autres petites molécules fluorés. L'extraction Soxhlet a ensuite été réalisée sur les électrodes permettant de révéler la présence d'un produit de dégradation hydrosoluble après fonctionnement en pile, à la fois en cathode et en anode. Enfin, la macération des électrodes dans le diméthylacétamide (DMAc) a permis d'extraire le polymère Nafion® ainsi que deux acides : l'acide trifluoroacétique (TFA) et l'acide triflique (TFI). En conclusion, la corrélation de l'ensemble des observations nous a permis de proposer un mécanisme de dégradation du liant ionomère présent dans les électrodes. / The purpose of this study was to follow the behavior of ionomer binder after fuel cell operation. First, a series of techniques were used to investigate to characterize ionomer in electrode at solid state. Most of them were inefficient to study ionomer degradation. Only X-Ray Diffraction (XRD) pointed out a structural change of the binder in electrodes. Second, it has been decided to characterize ionomer in liquid state after water extraction. But first of all, a quantitative 19F NMR protocol composed of two to three steps, with a first step using a quantification through signal-to-noise ratio (S/N), was establish in order to quantify Nafion® and degradation products. Soxhlet extraction performed on electrodes allowed to detect a degradation product water-soluble. Finally, extraction with organic solvent (Dimethylacetamide) allowed to extract Nafion® and two acid: trifluoroacetic acid (TFA) and triflic acid (TFI) from electrodes. In conclusion, correlation between observation and literature allowed us to propose a degradation mechanism of ionomer in electrodes.