Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The Pluchea sagittalis (Lam) Cabreira, Family Asteraceae, is a plant of the Atlantic Reainforest used in traditional medicine for the treatment of inflammation, as well as of digestive and respiratory diseases. The objective of this dissertation work was to study the possible effects of the aqueous extract of Pluchea sagittalis (Lam) Cabreira, on the Central Nervous System and acute toxicity in mice. This plant is used in traditional medicine for the treatment of inflammation, as well as of digestive and respiratory diseases. The Acute Toxicity (DL50) was gotten by the administration of the doses 1000, 2000 and 3000 mg/Kg, in according to legislation by National Agency of Sanitary Vigilance (ANVISA), but not being observed toxic effect. The possibilities of pharmacological actions had been analyzed by the test of screening pharmacological that showed the possible action of the extract as depress of the CNS. The antinociceptive effect was evaluated by using two models: acetic acid induced writhing and Tail-Flick test. In the first one was showed the analgesic effect of the extract with values of p > 0,01 in the dose of 200mg/Kg and p < 0,001 in the dose of 100 and 400 mg/Kg, when compared with the control group. The Tail-Flick test confirmed the analgesic effect of the extract with values of p<0,001, for all the doses, in the time of 30 and 60 minutes, with detach it 120 minutes after dose of 400 mg/Kg that kept p<0,001. On the sleep-induced by thiopental the extract was showed significance with p<0,05 at the return of the righting reflex and p<0,001, in the total time of sleep, for all the doses, with detach for the dose of 400 mg/Kg that showed the best effect. Thus the tests acetic acid induced writhing, Tail-Flick and sleep-induced by thiopental come to confirm the effect depress of this plant on the central nervous system initially identified for the screening pharmacological e for the traditional medicine. / A Pluchea sagittalis (Lam.) Cabrera, da Família Asteraceae, é uma planta da Mata Atlântica utilizada na medicina tradicional no tratamento de inflamação, assim como de doenças digestivas e respiratórias. O objetivo deste trabalho de dissertação foi estudar os possíveis efeitos do extrato aquoso das folhas de Pluchea sagittalis (Lam.) Cabrera, sobre o Sistema Nervoso Central em modelo murino, e, como a toxicidade aguda do extrato. A Toxicidade Aguda ou DL50 foi obtida pela administração das doses 1000, 2000 e 3000mg/Kg, segundo a legislação de medicamentos fitoterápicos da Agência Nacional de Vigilância Sanitária (ANVISA), não sendo observado efeito tóxico. As possibilidades de ação farmacológica foram analisadas pelo teste de triagem farmacológica que demonstrou a possível ação do extrato como depressor do SNC. O efeito anti-nociceptivo foi estudado usando dois modelos: Teste de Contorção abdominal induzida por ácido acético e Tail-Flick. No primeiro observou-se o efeito analgésico do extrato com valores de p<0,01 na dose de 200mg/Kg e p<0,001 nas de 100mg/Kg e 400mg/Kg, quando comparado ao grupo controle. O Tail-Flick confirmou o efeito analgésico do extrato com valores de p<0,001, nos tempos de 30 e 60 minutos para todas as doses, destacando-se a dose de 400mg/Kg que manteve p<0,001 após 120 min. No Teste de Tempo de Sono Induzido por Barbitúrico observou-se diferença significativa com p<0,05 para retornar o reflexo de endireitamento e p<0,001, no tempo total de sono, para todas as doses, com destaque para a dose de 400 mg/Kg que apresentou melhor efeito. Assim os testes de contorção abdominal, Tail-Flick e tempo de sono induzido por barbitúrico confirmaram o efeito depressor dessa planta sobre o sistema nervoso central identificado inicialmente pela triagem farmacológica e a medicina tradicional.

Made available in DSpace on 2015-05-14T13:21:40Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 9887169 bytes, checksum: df02b626a4888063d509afbbb46317e8 (MD5) Previous issue date: 2014-08-25 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / This work was presented using the technique of molecular hybridization which is a classic strategy in medicinal chemistry and useful in the design of new drugs, consisting of the covalent joining of two or more fragments known pharmacophoric or already present recognized therapeutic activities. Described the technique of extraction, isolation and purification of piperine 6 with 2% yield, with the same natural molecule mostly present in black pepper, where studies have shown a variety of biological activities as analgesic, anti-inflammatory, anti-thermal, antitumor, antifungal, antichagasic, insecticide, leishmanicidal, among others. Next, was performed the synthesis of the respective piperic acid 12 obtained via basic hydrolysis with 87% yield. A series of alcohols tetrahydropyran derivatives replaced (33, 34, 37, 38, 79 and 80) were synthesized in good yields (76% -100%), with synthetic route and potent antinociceptive already described by our group research. The Prins cyclization reaction was used as key step to build diastereoselective 2,4-cis and 2,4,6-cis tetrahydropyranyl rings. Subsequently, we performed the synthesis of 6 novel hybrid molecules (64, 65, 66, 67, 68 and 69), based on the structure of an analog of piperine (piperic acid) with 6 alcohols substituted tetrahydropyran derivatives, using the classical approach molecular hybridization by Steglich esterification reaction to join the two portions with relatively good yields (42% - 78%), which was the intention enhance the analgesic activity by these two chemical entities. All molecular hybrids were characterized by spectroscopic (1H and 13C) and IR / Neste trabalho foi apresentado o uso da técnica de hibridização molecular que é uma estratégia clássica em química medicinal e bastante útil na concepção de novos fármacos, consistindo na junção covalente de dois ou mais fragmentos reconhecidamente farmacofóricos ou que já apresentem atividades terapêuticas reconhecidas. Descreveu-se a técnica de extração, isolamento e purificação da piperina 6 com 2% de rendimento, sendo a mesma uma molécula natural presente principalmente na pimenta preta, onde estudos mostraram uma série de atividades biológicas como, analgésico, antiinflamatório, antitérmico, antitumoral, antifúngico, antichagásico, inseticida, leishmanicida, dentre outras. Em seguida, foi realizado a síntese do seu respectivo ácido pipérico 12 obtido via hidrólise básica com 87% de rendimento. Uma série de derivados álcoois tetraidropiranos substituídos (33, 34, 37, 38, 79 e 80) foram sintetizados em bons rendimentos (76%-100%), com rota sintética e potente atividade antinociceptiva já descritas pelo nosso grupo de pesquisa. A reação de ciclização de Prins foi usada como etapa chave para a construção, em forma diastereosseletiva 2,4-cis e 2,4,6-cis, dos anéis tetraidropiranos. Posteriormente, realizou-se a síntese de 6 moléculas híbridas inéditas (64, 65, 66, 67, 68 e 69), baseadas na estrutura de uma análogo da piperina (ácido pipérico) com os 6 derivados álcoois tetraidropiranos substituídos, utilizando a estratégia clássica de hibridização molecular através da reação de esterificação de Steglich para unir as duas porções, com rendimentos relativamente bons (42%-78%), onde o intuito foi potencializar a atividade analgésica apresentada por estas duas entidades químicas. Todos os híbridos moleculares foram caracterizados pelas técnicas de espectroscopia (1H e 13C) e infravermelho

Ce projet de recherche porte sur l’étude de la régulation des systèmes cannabinoïdes et vanilloïdes chez Caenorhabditis elegans (C. elegans), dans le but d’évaluer les effets antinociceptifs du tétrahydrocannabinol (THC) et du cannabidiol (CBD). C. elegans est un modèle largement utilisé pour étudier la nociception, visant principalement à caractériser les réponses nociceptives induites par le THC et le CBD, ainsi qu’à identifier les mécanismes et les cibles moléculaires impliqués. Les résultats des études sur l’utilisation du cannabis dans le traitement de la douleur chronique chez les mammifères sont controversés. Cette recherche vise à étudier l’effet du CBD et du THC sur la réponse nociceptive chez C. elegans et à approfondir la compréhension des mécanismes pharmacologiques sous-jacents. La méthodologie consiste à quantifier l’effet antinociceptif du CBD et du THC chez C. elegans par la méthode de la thermotaxie. Les nématodes sauvages (N2) étaient exposés à des concentrations croissantes de phytocannabinoïdes pour évaluer la relation concentration-effet. D’autres tests étaient effectués sur des souches mutantes exprimant des récepteurs cannabinoïdes et vanilloïdes afin d’identifier préalablement leurs cibles. Enfin, les analyses protéomiques et bioinformatiques seront effectuées pour identifier les voies de signalisation et les processus biologiques induits par l’interaction entre les phytocannabinoïdes et leurs cibles. Cette étude démontre l’activité antinociceptive du CBD et du THC chez C. elegans avec des effets rémanents pour THC, en ciblant respectivement le vanilloïde pour le CBD et le cannabinoïde pour les systèmes THC. Les analyses protéomiques et bio-informatiques mettent en évidence des différences significatives dans leurs voies de signalisation et leurs processus biologiques. / The objective of this research project was to focus on studying the regulation of cannabinoid and vanilloid systems in Caenorhabditis elegans (C. elegans) to evaluate the anti-nociceptive effects of tetrahydrocannabinol (THC) and cannabidiol (CBD). C. elegans is a widely used model for studying nociception, with the main objective being to characterize nociceptive responses induced by THC and CBD, as well as identify the underlying molecular mechanisms and targets involved. Recent studies on the use of cannabis for the treatment of chronic pain in mammals have shown controversial results. This research aims to investigate the effect of CBD and THC on the nociceptive response in C. elegans and understand the underlying pharmacological mechanisms. The methodology consisted in quantifying the antinociceptive effect of CBD and THC in C. elegans using the thermotaxis method. WT(N2) were exposed to decreasing concentrations of phytocannabinoids to evaluate the dose and effect relationship. Further tests performed on mutant expressing cannabinoid and vanilloid receptors allowed preliminarily identification of their targets. Finally, proteomic and bioinformatics analyses were used to identify the signaling pathways and biological processes induced by these phytocannabinoids. The result of this study confirmed the antinociceptive effect of CBD and THC in C. elegans, with a remanent effect of THC. This effect is mediated by the vanilloid system for CBD and the cannabinoid system for THC, respectively. Also, proteomics and bioinformatics analyses revealed significant differences in signaling pathways and biological processes.