Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

The thesis is focused on the effect of ghrelin receptor (GHS-R1a) agonists and antagonist on food intake regulation. Ghrelin is the only known periferally produced orexigenic hormone and the only known acylated hormone. GHS-R1a agonists and antagonists could be useful in the treatment of cachexia and obesity, respectively. In the first part of the thesis, newly designed peptidic GHS-R1a agonists were characterized. The agonists were stabilized by replacing octanoylated Ser3 with a fatty acid coupled to diaminopropionic acid by a stable amide bond. Other noncoded amino acids were also incorporated. Ghrelin analogs were modified by replacing the octanoyl group with another fatty acid, incorporation of the second fatty acid or shortening the peptide chain. Most of the tested GHS-R1a agonists were found to possess high affinities for GHS-R1a (Ki = 10-9 - 10-10 nM) and to activate signaling pathways of ghrelin. After subcutaneous (SC) administration to mice, agonists showed significant and prolonged orexigenic effect. In the second part of the thesis, acute and long-term effects of pseudopeptide GHS-R1a agonist JMV1843 were tested in lean C57BL/6 mice. Acute SC administration of JMV1843 to fed mice increased food intake in a dose-dependent manner (ED50 = 1.94 mg/kg). JMV1843 was stable in blood serum in...

The thesis is focused on the effect of ghrelin receptor (GHS-R1a) agonists and antagonist on food intake regulation. Ghrelin is the only known periferally produced orexigenic hormone and the only known acylated hormone. GHS-R1a agonists and antagonists could be useful in the treatment of cachexia and obesity, respectively. In the first part of the thesis, newly designed peptidic GHS-R1a agonists were characterized. The agonists were stabilized by replacing octanoylated Ser3 with a fatty acid coupled to diaminopropionic acid by a stable amide bond. Other noncoded amino acids were also incorporated. Ghrelin analogs were modified by replacing the octanoyl group with another fatty acid, incorporation of the second fatty acid or shortening the peptide chain. Most of the tested GHS-R1a agonists were found to possess high affinities for GHS-R1a (Ki = 10-9 - 10-10 nM) and to activate signaling pathways of ghrelin. After subcutaneous (SC) administration to mice, agonists showed significant and prolonged orexigenic effect. In the second part of the thesis, acute and long-term effects of pseudopeptide GHS-R1a agonist JMV1843 were tested in lean C57BL/6 mice. Acute SC administration of JMV1843 to fed mice increased food intake in a dose-dependent manner (ED50 = 1.94 mg/kg). JMV1843 was stable in blood serum in...

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La ghréline, une hormone peptidique principalement synthétisée au niveau de l'estomac, est le ligand endogène du récepteur des sécrétagogues de l'hormone de croissance appelé GHS-R1a. Elle est impliquée dans de nombreux processus biologiques dont principalement la sécrétion de l'hormone de croissance et la régulation de l'homéostasie énergétique. En raison de ses propriétés orexigènes et adipogènes, la ghréline est un outil puissant pour lutter contre les déséquilibres énergétiques. Développer des antagonistes de son récepteur représente ainsi une stratégie prometteuse pour la découverte de nouvelles pharmacothérapies contre l'obésité.Cette thèse est consacrée au développement d'antagonistes du récepteur de la ghréline dont la structure est basée sur une plateforme peptidomimétique : le 1,2,4-triazole 3,4,5-trisubstitué. Notre objectif est de concilier au mieux l'affinité et l'activité de nos ligands vis-à-vis du GHS-R1a avec des propriétés optimisées permettant de favoriser une bonne biodisponibilité orale. Nous nous sommes basés sur une synthèse rapide et efficace de ces composés pour réaliser des études approfondies de relations structure-activité et structure-propriété. En optimisant successivement les différentes positions autour du motif triazole, des compromis intéressants ont été obtenus. Nous avons ainsi identifié des antagonistes affins du récepteur qui présentent une stabilité microsomale suffisante et une perméabilité membranaire satisfaisante pour envisager des études in vivo. / Ghrelin, a peptidic hormone which is mainly synthesized in the stomach, is the endogenous ligand of the growth hormone secretagogue receptor named GHS-R1a. It is involved in numerous biological processes such as the growth hormone secretion and the control of energy homeostasis. Because of its orexigenic and adipogenic properties, ghrelin is a potent tool to control energy imbalance. Developing ghrelin receptor antagonists represents a promising strategy for the discovery of anti-obesity new drugs.This thesis is devoted to the development of ghrelin receptor antagonists based on a peptidomimetic scaffold: the 3,4,5-trisubstituted 1,2,4-triazole. Our aim is to combine ligand affinity and activity towards GHS-R1a with optimized properties which enable to promote a good oral bioavailability. We based our work on a rapid and efficient synthesis of our compounds to carry out detailed structure-activity and structure-property studies. By successively optimizing the different positions around the triazole scaffold, interesting compounds were obtained. We have thus identified receptor antagonists which exhibit sufficient microsomal stability and satisfactory membrane permeability to consider in vivo studies.

Com o aumento gradativo da tecnologia e da necessidade de consumo humana, a cada dia são desenvolvidos novos produtos e novas substâncias. Além dos benefícios desta modernização, surgem as preocupações relacionadas com o uso excessivo de produtos químicos. Muitos produtos químicos possuem potencial de causar efeitos adversos à saúde humana e ao meio ambiente e, por isso, de uns anos pra cá, passou a ser essencial e obrigatória a comunicação dos riscos advindos desses produtos dentro do ambiente de trabalho. O GHS, um sistema globalmente harmonizado de classificação e rotulagem de produtos químicos foi criado pela ONU para trazer critérios e elementos harmonizados para a comunicação desses perigos. A identificação dos perígos do GHS é um procedimento complexo e muito difícil para as empresas, com destaque para aquelas de menor porte, como é o exemplo do setor de saneantes, que é, em sua maioria, constituido por micro e pequenas empresas. Além de terem a obrigação de seguir os requisitos estabelecidos pelo GHS, os fabricantes de saneantes seguem as exigências da Anivsa para comercialização de seus produtos. Combinando os requisitos da Anvisa com os do GHS, percebe-se que algumas classes e categorias de perigo do GHS não se aplicam para saneantes. Com isso, o propósito desse trabalho foi desenvolver um roteiro para classificação do GHS destinado especificamente ao setor de saneantes. Para o desenvolvimento do roteiro foram elaborados fluxogramas de decisões lógicas com requisitos do GHS e exigências da Anvisa. O trabalho atingiu o seu objetivo como um todo, criando um modelo de roteiro para aplicação do GHS para o setor de saneantes. Após a aplicação do roteiro em um produto exemplo e após as discussões levantadas, percebeu-se que alguns detalhes poderiam ser melhor incorporados no roteiro. Apesar do roteiro possuir suas limitações e algumas imperfeições, acredita-se que possa contribuir de alguma forma para o setor. Ao invés dos profissionais consultarem o GHS como um todo, um guia simplificado, resumido e com particularidades do setor, pode fazer com que as indústrias tenham uma maneira mais fácil de aplicar o GHS e, assim, contribuir para que as classificações sejam realizadas de uma maneira correta. / With the technology gradual increase and the need of human consumption every day new products and new substances are developed. In addition to the benefits of this modernization, there are concerns about the excessive use of chemicals. Many chemicals have potential to cause adverse effects on human health and the environment and, therefore, a few years ago the risk communication of these products in a workplace became essential and mandatory. The GHS, a globally harmonized system of classification and labeling of chemicals was created by the UN to bring harmonized criteria and elements to communicate these dangers. The GHS hazard identification is a complex and difficult procedure for the industries, especially those ones that are small, as sanitizer sector for example, which is mostly composed of micro and small companies. In addition to have the GHS obligation the sanitizer manufacturers follow the Anvisa regulation as well. Combining the Anvisa requirements with GHS ones, it is clear that some GHS hazard classes and categories do not apply for cleaning products. Thus, the purpose of this study was to develop a GHS classification guide intended specifically for sanitizer industry. To build the guide flowcharts were developed with logical decisions with GHS and Anvisa requirements. This study reached its goal as a whole, creating a guide model for GHS implementation in sanitizer industries. After the guide application in a product sample and the discussions, it was noted that some details could be better incorporated into the script of the guide. Although the guide has some limitations and imperfections, it can contribute in some way to the industry. Instead of a professional consulting GHS as a whole, a simplified, summarized and with the sanitizer particularities guide may give to the industries an easier way to apply the GHS contributing to the correct classifications.

Com o aumento gradativo da tecnologia e da necessidade de consumo humana, a cada dia são desenvolvidos novos produtos e novas substâncias. Além dos benefícios desta modernização, surgem as preocupações relacionadas com o uso excessivo de produtos químicos. Muitos produtos químicos possuem potencial de causar efeitos adversos à saúde humana e ao meio ambiente e, por isso, de uns anos pra cá, passou a ser essencial e obrigatória a comunicação dos riscos advindos desses produtos dentro do ambiente de trabalho. O GHS, um sistema globalmente harmonizado de classificação e rotulagem de produtos químicos foi criado pela ONU para trazer critérios e elementos harmonizados para a comunicação desses perigos. A identificação dos perígos do GHS é um procedimento complexo e muito difícil para as empresas, com destaque para aquelas de menor porte, como é o exemplo do setor de saneantes, que é, em sua maioria, constituido por micro e pequenas empresas. Além de terem a obrigação de seguir os requisitos estabelecidos pelo GHS, os fabricantes de saneantes seguem as exigências da Anivsa para comercialização de seus produtos. Combinando os requisitos da Anvisa com os do GHS, percebe-se que algumas classes e categorias de perigo do GHS não se aplicam para saneantes. Com isso, o propósito desse trabalho foi desenvolver um roteiro para classificação do GHS destinado especificamente ao setor de saneantes. Para o desenvolvimento do roteiro foram elaborados fluxogramas de decisões lógicas com requisitos do GHS e exigências da Anvisa. O trabalho atingiu o seu objetivo como um todo, criando um modelo de roteiro para aplicação do GHS para o setor de saneantes. Após a aplicação do roteiro em um produto exemplo e após as discussões levantadas, percebeu-se que alguns detalhes poderiam ser melhor incorporados no roteiro. Apesar do roteiro possuir suas limitações e algumas imperfeições, acredita-se que possa contribuir de alguma forma para o setor. Ao invés dos profissionais consultarem o GHS como um todo, um guia simplificado, resumido e com particularidades do setor, pode fazer com que as indústrias tenham uma maneira mais fácil de aplicar o GHS e, assim, contribuir para que as classificações sejam realizadas de uma maneira correta. / With the technology gradual increase and the need of human consumption every day new products and new substances are developed. In addition to the benefits of this modernization, there are concerns about the excessive use of chemicals. Many chemicals have potential to cause adverse effects on human health and the environment and, therefore, a few years ago the risk communication of these products in a workplace became essential and mandatory. The GHS, a globally harmonized system of classification and labeling of chemicals was created by the UN to bring harmonized criteria and elements to communicate these dangers. The GHS hazard identification is a complex and difficult procedure for the industries, especially those ones that are small, as sanitizer sector for example, which is mostly composed of micro and small companies. In addition to have the GHS obligation the sanitizer manufacturers follow the Anvisa regulation as well. Combining the Anvisa requirements with GHS ones, it is clear that some GHS hazard classes and categories do not apply for cleaning products. Thus, the purpose of this study was to develop a GHS classification guide intended specifically for sanitizer industry. To build the guide flowcharts were developed with logical decisions with GHS and Anvisa requirements. This study reached its goal as a whole, creating a guide model for GHS implementation in sanitizer industries. After the guide application in a product sample and the discussions, it was noted that some details could be better incorporated into the script of the guide. Although the guide has some limitations and imperfections, it can contribute in some way to the industry. Instead of a professional consulting GHS as a whole, a simplified, summarized and with the sanitizer particularities guide may give to the industries an easier way to apply the GHS contributing to the correct classifications.

Ghrelin analogs in food intake regulation Ghrelin, to date the only known peripherally produced and centrally acting peptide that stimulates food intake, is mainly synthesized in the stomach and acts through growth- hormone-secretagogue receptor (GHS-R). In addition to its orexigenic effect, ghrelin stimulates growth hormone (GH) release, gastric motility and acid secretion. The diverse functions of ghrelin raise the possibility of its clinical application for GH deficiency, eating disorders, and gastrointestinal diseases. Ghrelin agonists could be a promising therapeutics in cachexia occurring at cancer or chronic inflammatory diseases. Octanoylation of Ser3 is crucial for preservation of ghrelin activity. In this study, biological properties (binding to GHS-R, food intake stimulation in mice) of full length and shorter ghrelin analogues with octanoic acid coupled to diaminopropionic acid (Dpr) replacing Ser3 or without octanoic acid were followed. This substitution resulted in a prolonged stability and orexigenic effect of above mentioned ghrelin analogues. Importance of N-terminal part of ghrelin and octanoylation peptide was also confirmed.

This diploma thesis deals with the problem of ecological design and optimization of electrical products. The theoretical part describes the ecodesign legislation and assessment tools. The practical part is deals with created software for evaluation and comparison of electrical products. I analyzed three flash drives, which are commonly used. In these flash drives analyze packages and these packages were evaluated and compared with software. The last section describes the problems of availability of the necessary information.

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No. of bitstreams: 2 Dissertação - Gabriel Camargo da Silva - 2016.pdf: 2237673 bytes, checksum: f750ddf2e821b6d6b8bc80eae327232d (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2016-10-28 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Ghrelin is a 28 amino acid peptide described at 90’s. Within its multiple functions, production of growth hormone (GH), food intake, cell proliferation, regulation of cardiovascular system and behavior may be highlighted. Ghrelin actions are mediated by the growth hormone secretagogue receptor subtype 1a (GHS-R1a), which is distributed along several peripheral tissues and central areas involved in the control of cardiovascular responses to aversion. Since GHS-Rs1a is expressed in central areas that govern cardiovascular responses to aversion, our aim was to assess the role of Ghrelin in the cardiovascular reactivity to acute emotional stress. Adult male Wistar rats (250-350g) underwent acute emotional stress following i.v. injection of ghrelin (1 or 10 µg/kg), the antagonist of GHS-R1a (PF04628935) or vehicle (VHE). We further investigated the cardiac beta-adrenergic sensitivity in vivo by injecting isoproterenol (1 µg/kg) and ghrelin (10 µg/kg). Autonomic blockade was reached by subsequent injections of atenolol (4 mg/kg), methylatropine (3 mg/kg), ghrelin (10 µg/kg) e VHE. Finally, we evaluated in isolated hearts the effects of perfusion with ghrelin (0.2nMol/L) followed by crescent bolus concentrations of isoproterenol and acetylcholine. Current findings show that ghrelin potentiates the tachycardia evoked by restraint and by air jet stress. We demonstrated that administration of ghrelin improves beta-adrenergic sensitivity in vivo and ex vivo. Autonomic blockade experiments revealed that autonomic nervous system, through sympathetic branch, modulates the stress-evoked positive chronotropy. Furthermore, perfusion of isolated hearts with ghrelin resulted in positive inotropy and potentiated contractile responses caused beta-adrenergic agonism, without altering the amplitude of the responses evoked by acetylcholine. In conclusion, administration of ghrelin and the consequent activation of GHS-R1a increased the magnitude of the tachycardia evoked by acute emotional stress by modulating autonomic nervous system and through peripheral mechanisms, strongly dependent on activation of cardiac beta-adrenergic receptors. / A grelina é um peptídeo de 28 aminoácidos identificado no fim da década 90. Dentre suas várias funções, destacam-se a produção do hormônio de crescimento (GH), os efeitos sobre o apetite, proliferação celular, participação no sistema cardiovascular e regulação do comportamento. Sua ação se dá pela ligação ao receptor secretagogo do hormônio do crescimento subtipo 1a (GHS-R1a) distribuído em vários tecidos periféricos e em algumas regiões do sistema nervoso central (SNC) envolvidas na modulação cardiovascular durante eventos aversivos. Sabendo que os GHS-R1a são distribuídos em áreas centrais que modulam as respostas cardiovasculares durante eventos aversivos, o objetivo do nosso trabalho foi avaliar o papel da grelina nas respostas cardiovasculares evocadas por estresse emocional agudo. Ratos Wistar (250-350g) foram submetidos ao estresse emocional agudo após administração i.v. de grelina (1 ou 10 µg/kg), antagonista de GHS-R1a (PF04628935) ou veículo (VHE).Também avaliamos a sensibilidade beta adrenérgica cardíaca in vivo com administrações de isoproterenol na dose 1 µg/kg e grelina (10 µg/kg). O bloqueio autonômico cardíaco foi realizado com administrações de atenolol (4 mg/kg), metilatropina (3 mg/kg), grelina (10 µg/kg) e VHE. Por fim, avaliamos em corações isolados os efeitos da perfusão com grelina na concentração de 0,2 nMol, seguida de administrações in bolus de concentrações crescentes de isoproterenol e acetilcolina. Os achados demonstram que a grelina potencia a taquicardia evocada pelo estresse por contenção e por jato de ar. Demonstramos que a administração de grelina promove um aumento da sensibilidade beta adrenérgicai n vivo e ex vivo. Os experimentos de bloqueio autonômico revelaram que o sistema nervoso central, através do eixo simpático, modula a resposta taquicárdica pela administração de grelina. Além disso, a perfusão de corações isolados com grelina promoveu um aumento da contratilidade cardíaca e potenciação da resposta ao agonismo beta adrenérgico, sem alterar a resposta à acetilcolina. Em conclusão, a administração de grelina e subsequente ativação de GHS-R1a potencia a taquicardia evocada por estresse emocional agudo através da modulação do sistema nervoso central e de mecanismos periféricos, dependentes da ativação de receptores beta adrenérgicos cardíacos.