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Direct ethanol fuel cells are of interest due to the high energy density, ease of distribution and handling, and low toxicity of ethanol. Difficulties lie in finding a catalyst that can completely oxidize ethanol and resist poisoning by intermediate reaction species. Degradation of the catalyst layer over time is also an issue that needs to be addressed. In this work, niobium doped-titanium dioxide (Nb-TiO2) is investigated as a platinum (Pt) support due to its increased resistance to corrosion compared to the common catalyst support, carbon. It has also been seen in the literature that TiO2 is able to adsorb OH and assist in freeing Pt sites by further oxidizing COad to CO2 and thereby increasing the catalytic activity of catalysts toward ethanol oxidation. The TiO2 support is mixed with carbon, forming Nb-TiO2-C, in order to increase the conductivity throughout the support. The electrochemical activity and direct ethanol fuel cell (DEFC) performance of this novel catalyst is investigated and compared to that of two common catalysts, carbon supported Pt (Pt/C) and carbon supported platinum-tin (PtSn/C). While the conductivity of the Pt/Nb-TiO2-C electrodes was low compared to that of the carbon supported electrodes, the overall catalytic activity and performance of the TiO2 supported catalyst was comparable to that of the Pt/C catalyst based on the electrochemically active surface area. / Master of Science

Synucleins are highly conserved presynaptic proteins with unknown function. α-synuclein plays a key role regulating dopamine homeostasis and is intimately involved in Parkinson’s disease (PD) pathogenesis. However, the normal/pathological role of α-synuclein remains unidentified. Studies exploring its function are limited as current transgenic mouse models do not fully recapitulate PD pathology. This thesis reports the functional characterisation of two novel synuclein-based mouse models. I report the molecular and functional characterisation of transgenic mouse lines with wild-type or A30P-mutant human α-synuclein genomic locus carried within a bacterial artificial chromosome. SNCA-A30P^+Snca-/- mice exhibited a highly physiologically relevant expression pattern of the transgene, including expression in the substantia nigra pars compacta (SNpc) and a specific, age-related loss of TH^+ cells in the SNpc, the key region of preferential cell loss in PD, compared with non-transgenic Snca -/- littermate controls. Analysis of dopamine signalling using fast-scan cyclic voltammetry (FCV) showed young adult SNCA-A30P^+Snca-/- mice had an approximately 20% lower evoked extracellular dopamine concentration ([DA]o) compared with non-transgenic Snca -/- littermate controls, a decrease specific to the dorsal striatum. This difference diminished with age and could not be attributed to changes in dopamine reuptake/content. I detail the behavioural and neurochemical phenotype in mice lacking all three synucleins (α/β/γ). Functional compensation between synucleins emphasises the importance of studying their effects by removing all three proteins simultaneously. Triple-null mice exhibited hyperactivity in a novel environment reminiscent of a hyperdopaminergic-like phenotype, but showed no phenotype in anxiety or motor related tests. FCV revealed synuclein triple-null mice had a two-fold increase in [DA]o, specific to the dorsal striatum and not attributable to changes in dopamine reuptake/content, changes in striatal nicotinic receptor activity nor calcium-dependent changes in dopamine exocytosis. Together, the analysis from these two novel mouse models reveal synucleins play an important role in altering synaptic function in the dorsal striatum (the region selectively affected in PD) and contributes to growing evidence suggesting synucleins are negative regulators of synaptic dopamine release.

This thesis presents the results and discussion of the investigation of the effects of Brönsted bases on the kinetics and thermodynamics of two proton-coupled electron transfer processes: the mediated oxidation of glutathione and the electrochemical oxidation of hydroquinone. Proton-coupled electron transfer (PCET) is the name given to reactions that involve the transfer of electron(s) accompanied by the exchange of proton(s). PCETs are found in many chemical and biological processes, some of current technological relevance such as the oxygen reduction reaction in fuel cells, which involves the transfer of four electrons and four protons (4e-, 4H+); or the splitting of water into protons (4H+), electrons (4e-) and oxygen (O2) efficiently achieved in photosynthesis. The study of PCET mechanisms is imperative to understanding biological processes as well as to developing more efficient technological applications. However, there are still many unanswered questions regarding the kinetic and thermodynamic performance of PCETs, and especially about the effect of different proton acceptors on the rate and mechanism of PCET reactions. This study aimed to investigate the effect of Brönsted bases as proton acceptors on the kinetics and thermodynamics of two model PCET processes, the oxidation of glutathione and hydroquinone. The analysis presented in this thesis provides insight into the influence of different proton acceptors on the mechanism of PCET and it does so by studying these reactions from a different angle, that one of the acid-base catalysis theory which has been successfully applied to the investigation of numerous chemical reactions coupled to proton transfer. We hope future research of PCETs can benefit from the knowledge of acid-base catalysis to better understand these reactions at a molecular level.

Neste trabalho foi realizada a funcionalização de grafite sem prévio tratamento em condições de Fridel-Crafts. Considerando que a grafite não possui hidrogênio em sua estrutura, não se observa uma reação de substituição eletrofílica. Por outro lado, o trabalho mostra o papel da umidade presente no grafite na reação de funcionalização. Dessa forma, foi proposto um mecanismo para a reação com a participação da água adsorvida na grafite estabilizando o carbocátion formado. O grafite funcionalizado obtido na reação foi utilizado como material eletródico. Para a reação de funcionalização, quatro moléculas foram utilizadas: ácido ferrocenomonocarboxílico, cloreto de 4-nitrobenzoíla, cloreto de 3,5-dinitrobenzoíla e ácido 3,4-dinitrobenzóico. Para o estudo das condições ótimas da reação, utilizou-se diferentes potências de radiação no reator de micro-ondas, sendo que a extensão da funcionalização mostrou-se sensível à variação deste parâmetro. Para a caracterização dos materiais, utilizou-se voltametria cíclica e análise térmica (TG e DTA). Resultados de infravermelho e Ramam são apresentados no Apêndice A. Os resultados eletroquímicos mostraram que os materiais funcionalizados em maiores potências apresentaram maior corrente Faradaica, mas ao mesmo tempo, o material obtido foi mais resistivo. A diferença de potencial relacionada ao processo redox do ferroceno aumentou conforme a extensão da funcionalização, uma vez que um sobrepotencial é necessário devido ao fluxo iônico (para a manutenção da eletroneutralidade) relativo ao número de espécies envolvidas. Os resultados eletroquímicos também indicaram que a funcionalização do grafite com os nitro compostos foi baixa. A análise térmica evidenciou que a reação de funcionalização do grafite com o ferroceno resultou em materiais com 15% a 20% (m/m) de material ligado ao grafite. Os materiais funcionalizados a maiores potências apresentaram maior massa ligada ao grafite. A funcionalização com os nitro compostos resultou em materiais com menos de 3% (m/m) de composto ligado ao grafite. Os resultados das duas técnicas mostraram coerência na análise da extensão da funcionalização. O material funcionalizado com o ácido ferrocenomonocarboxilico foi o que apresentou os melhores resultados e propõe-se uma explicação para tal baseado no mecanismo de reação sugerido. Com o objetivo de melhor elucidar o mecanismo da reação, foram realizadas algumas reações na ausência de alguns reagentes. Por exemplo, quando tenta-se funcionalizar o material sem a presença de cloreto de alumínio ou sem a umidade natural do grafite, a reação não ocorre. / In this work natural graphite functionalization in Fridel-Crafts conditions is performed using a one-step microwave assisted reaction. Since there is no hydrogen in graphite structure, it is not possible to observe electrophilic substitution. On the other hand this work shows the role of the moisture present on graphite in the functionalization reaction under this condition. Therefore, a reaction mechanism with the participation of the water naturally adsorbed on graphite stabilizing the formed carbocation has been suggested. After the reaction, the functionalized graphite was used as electrode material. Four molecules were used to functionalize graphite: Ferrocene monocarboxylic acid, 4-nitrobenzoyl chloride, 3,5-dinitrobenzoyl chloride and 3,4-dinitrobenzoic acid. To study the optimal conditions of the reaction, the microwave radiation power was varied and the extent of the functionalization on graphite was sensitive to this parameter. Two techniques were used to characterize the materials, cyclic voltammetry and thermal analysis (TG and DTA). IR and Raman data are shown in appendix A. Electrochemical results have shown that the materials functionalized at higher microwave radiation power have higher Faradaic current, but are more resistive. The potential difference between the peaks of the redox process of ferrocene increased with the extent of functionalization. This occurs because an overpotencial is needed to compensate the ionic flux (in order to maintain the electroneutrality) related to the number of species involved. The electrochemical results also indicated that the extent of functionalization of graphite with the nitro compounds was low. The thermal analysis have shown that the functionalization of graphite with ferrocene lead to values between 15% to 20% (m/m) of compound in the material. The materials functionalized at higher microwave radiation power presented higher relative mass in the material. The reaction with the nitro compounds lead to less than 3% (m/m) of compound in the final material. The results of both techniques were coherent about the extent of functionalization. The material functionalized with ferrocene monocarboxylic acid showed the best results, and an explanation for that based on the reaction mechanism is suggested. In order to elucidate the reaction mechanism, some experiments were realized in absent of some reagents. When the reaction were carried out without aluminum chloride or with dried graphite, the reaction has not occurred.

Eletrodos à base de carbono, como os eletrodos de troca iônica, entre outros, têm aplicação principalmente no tratamento de efluentes industriais e rejeitos radioativos. Carbono é também amplamente utilizado em células a combustível como substrato para os eletrocatalisadores, por possuir elevada área superficial, que supera a sua área geométrica. O conhecimento desta superfície ativa total é importante na determinação das condições de operação de uma célula eletroquímica no que diz respeito às correntes a serem aplicadas (densidade de corrente). No presente estudo foram utilizadas duas técnicas eletroquímicas na determinação da área superficial ativa de eletrodos de carbono vítreo e poroso e eletrodos de troca iônica: espectroscopia de impedância eletroquímica (EIE) e voltametria cíclica (VC). Os experimentos foram realizados com soluções de KNO3 0,1 mol.L-1 em célula eletroquímica de três eletrodos: eletrodo de trabalho à base de carbono, eletrodo auxiliar de platina e eletrodo de referência de Ag/AgCl. Os eletrodos de carbono vítreo e de carbono poroso utilizado possuíam uma área geométrica de 3,14 x 10-2 cm2 e 2,83 10-1 cm2, respectivamente. O eletrodo de troca iônica foi preparado misturando-se grafite, carbono, resina de troca iônica e um aglutinante, sendo esta mistura aplicada em três camadas sobre feltro de carbono, utilizando-se nos experimentos uma área geométrica de 1,0 cm2. Por EIE determinou-se diretamente a capacitância dos materiais dos eletrodos (Cd) utilizando-se os diagramas de Bode. O valor de 172 μF.cm-2 encontrado para o carbono vítreo está de acordo com a literatura (~200 μF.cm-2). Por VC, variando a velocidade de varredura de 0,2 a 2,0 mV.s-1, determinou-se a capacitância CdS (S=área superficial ativa) na região da dupla camada elétrica (DCE) para cada um dos materiais, Por EIE, foram determinados os valores de Cd de 3,0 x 10-5 μF.cm-2 e de 11,0 x 103 μF.cm-2 para os eletrodos de carbono poroso e de troca iônica, respectivamente, o que possibilitou a determinação das áreas superficiais ativas de 3,73 x 106 cm2 e 4,72 cm2. Portanto, o uso combinado das técnicas de EIE e VC mostra-se promissor para o cálculo das áreas superficiais ativas de eletrodos à base de carbono. / Carbon-based electrodes as well the ion exchange electrodes among others have been applied mainly in the treatment of industrial effluents and radioactive wastes. Carbon is also used in fuel cells as substrate for the electrocatalysts, having high surface area which surpasses its geometric area. The knowledge of the total active area is important for the determination of operating conditions of an electrochemical cell with respect to the currents to be applied (current density). In this study it was used two techniques to determine the electrochemical active surface area of glassy carbon, electrodes and ion exchange electrodes: cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The experiments were carried out with KNO3 0.1 mol.L-1 solutions in a three-electrode electrochemical cell: carbon-based working electrode, platinum auxiliary electrode and Ag/AgCl reference electrode. The glassy carbon and porous carbon electrodes with geometric areas of 3.14 x 10-2 and 2.83 10-1 cm2, respectively, were used. The ion exchange electrode was prepared by mixing graphite, carbon, ion exchange resin and a binder, and this mixture was applied in three layers on carbon felt, using a geometric area of 1.0 cm2 during the experiments. The capacitance (Cd) of the materials was determined by EIS using Bode diagrams. The value of 172 μF.cm-2 found for the glassy carbon is consistent with the literature data (~200 μF.cm-2). By VC, varying the scan rate from 0.2 to 2.0 mV.s-1, the capacitance CdS (S = active surface area) in the region of the electric double layer (EDL) of each material was determined. By EIS, the values of Cd, 3.0 x 10-5 μF.cm-2 and 11 x 103 μF.cm-2, were found for the porous carbon and ion exchange electrodes, respectively, which allowed the determination of active surface areas as 3.73 x 106 cm2 and 4.72 cm2. To sum up, the combined use of EIS and CV techniques is a valuable tool for the calculation of active surface areas of carbon-based electrodes.

Introduction: Over recent decades, there has been an increase in the availability and use of Novel Psychoactive Substances (NPS) all over the world. They include several classes of chemicals that mimic the effects of illicit drugs and have been purposefully introduced into the market to circumvent or undermine the purpose of legal regulation. Currently, there is information lacking on the pharmacology of these substances; however, the increasing number of cases and outbreaks of intoxications/deaths is becoming a cause for deepening concern. Multi-disciplinary research in the fields of biology, chemistry, clinical medicine and web analysis is needed to develop responses against this tidal wave. Aim: The overall aim of this project is to gain insights into pharmacological, neurochemical and molecular properties of selected NPS to provide a reliable background needed for detection, assessment, and management of NPS-related harms. A range of approaches and methodologies was employed and a spectrum of different fields of knowledge has been engaged to gain some understanding into the complex multi-faceted phenomenon of NPS. Methods: Different substances have been selected as targets for the present project according to the clinical pattern of toxicity raised by their worldwide use and the lack of scientific knowledge available about them. The methods employed were: in vitro quantitative autoradiography (to evaluate the binding properties of the novel SCs BB-22, 5F-PB-22, 5F-AKB-48 and STS-135 at the cannabinoid receptor type 1 and N-methyl-D-aspartate receptor; and the binding properties of the synthetic stimulants 5-IT and 2-DPMP at the dopamine transporter in rat brain slices); in vitro Fast Scan Cyclic Voltammetry (to assess the effects of BB-22 on evoked dopamine efflux and dopamine re-uptake half-life in nucleus accumbens brain slices); in vivo microdialysis (to monitor dopamine release in terminal areas of the reward system after acute administration of the synthetic cannabinoids BB-22, 5F-PB-22, 5F-AKB-48 and STS-135; the dieting aid compound 2,4-DNP; the synthetic stimulants 2-DPMP and D2PM in freely moving animals); in silico molecular docking (to investigate the intermolecular interactions of the SCs BB-22, 5F-PB-22, 5F-AKB-48 and STS-135, and other referent compounds, with a homology model of the rodent cannabinoid receptor type 1 (CB1R) and the crystal structure of the human CB1R); and a web-based analysis approach (to analyse the information provided by a range of fora communities on 4,4'-DMAR use, additionally critical reviewing the available evidence-based literature on this topic). Results: Our in vitro quantitative autoradiography studies, confirmed that the index compounds BB-22, 5F-PB-22, 5F-AKB-48 and STS-135, behave as highly potent CB1R ligands able to compete with the radioligand [3H]CP-55,940 in cortical and striatal brain slices. On the other hand, all synthetic cannabinoids tested were unable to compete with the radioligand [3H]MK-801 in the same cerebral areas, rejecting the hypothesis of their potential binding to the N-methyl-D-aspartate receptor (NMDAR) at all concentrations investigated. Consistent with previous in vitro studies, 5-IT and 2-DPMP behaved as highly potent dopamine transporter (DAT) ligands able to compete with the radioligand [125 I]RTI-121 in a concentration-dependent way in the Caudate Putamen (CPu) and Nucleus Accumbens (NAc) brain slices. Notably, 2-DPMP was able to displace the radioligand in both cerebral regions, starting from lower concentrations compared to 5-IT. In vitro Fast Scan Cyclic Voltammetry findings demonstrated that local application of the synthetic cannabinoid BB-22 in brain slices, was unable to change evoked dopamine efflux and dopamine reuptake time-constant in the NAc shell at any doses tested. The results obtained would suggest the relative contributions of complex neuronal circuits, either within or outside the NAc, whose modulation would interfere with the interactions between BB-22 and dopaminergic neurons and represent critical pathways accounting for some of the rewarding properties of BB-22 exposure. In vivo microdialysis outcomes suggested that all SCs tested could increase dopamine release in the NAc shell at specific doses, while no changes in dopamine output were observed in other areas of the reward system, namely NAc core and medial prefrontal cortex (mPFCx) after BB-22 administration. These outcomes provided a circumstantial pre-clinical evidence for a greater putative abuse liability of SCs compared to the natural compound found in cannabis (Δ9‐THC). Furthermore, the acute treatment with 2,4-DNP did not cause any change in dopamine release in the NAc shell and CPu rejecting the hypothesis of psychoactivity of this substance at the dose tested. On the other hand, the synthetic stimulant 2-DPMP elicited a comparable increase of dopamine (DA) release in the NAc shell and CPu at the higher doses tested, while D2PM caused a selective increase of DA release in the NAc shell, providing a circumstantial preclinical evidence for a putative abuse liability of this compound at the highest dose assessed. The in silico molecular docking studies demonstrated that the SCs BB-22, 5F-PB-22, 5F-AKB-48 and STS-135 interact with CB1 receptor residues that, according to previous mutation and computational studies, are considered crucial for synthetic cannabinoid binding recognition. Additionally, they share some interacting residues with other aminoalkylindole derivatives (e.g. WIN-55,212-2). The web-based analysis focused on 4,4'-DMAR, suggested that fora members co-operate in exchanging an extensive body of knowledge about this drug, and the recurring topics of discussion include: routes of administration and dosages; desired and undesired effects; comparison and association with other drugs and medications; overall impression; provision of harm reduction advice. This approach has been useful to better understand some of the clinical and psychopharmacological issues pertaining to 4,4'-DMAR. Conclusions: Overall, these studies provided new pharmacological, neurochemical and molecular knowledge on a range of Novel Psychoactive Substances essential for identifying potential therapeutical approaches against their use/abuse. The novelty of this project lies in the adoption of a multi-disciplinary approach involving a range of methodologies from different areas of expertise (neurobiology, pharmacology, chemistry, netnography) all integrated to clarify some aspects of the index NPS, which were not yet available in the current literature. Additional studies are needed to better explain short and long-term effects of the index NPS, their abuse potential, and their interactions with other drugs of abuse.