Avaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto híbrido cis-(±)-acetato de 4-cloro-6-(naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2- (2-(2,6-diclorofenilamino) fenila

Detalhes bibliográficos
Autor(a) principal: Gonçalves, Gabriela Mastrangelo
Data de Publicação: 2020
Tipo de documento: Tese
Idioma: por
Título da fonte: Biblioteca Digital de Teses e Dissertações da UFRRJ
Texto Completo: https://rima.ufrrj.br/jspui/handle/20.500.14407/9431
Resumo: A hibridação molecular é uma estratégia clássica de conjugação de estruturas de compostos bioativos distintos em uma única molécula, sendo uma alternativa eficaz de arquitetar racionalmente novos compostos que podem apresentar sinergismo e terapia de dupla ação farmacológica ou modulação de efeitos adversos. O objetivo deste estudo foi avaliar a atividade antinociceptiva e anti-inflamatória de um novo composto híbrido: cis - (±) - acetato de 4-cloro-6- (naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2- (2-(2,6-diclorofenilamino) fenila (LS19), obtido através da hibridização do composto [(±)-(2,4,6-Cis)-4-cloro-6-(naftaleno-1-il)-tetrahidro-2H-pirano-2-il] metanol (CAPIM e cols., 2012) com o anti-inflamatório não-esteroidal diclofenaco de sódio. O composto LS19 foi administrado por via oral em todos os modelos animais e de acordo com os resultados, possui atividade contra a nocicepção aguda observada nos modelos de contorções abdominais induzidas por ácido acético, teste de formalina e imersão da cauda em água quente. O mecanismo de ação do composto envolve o sistema opioide, já que antagonistas seletivos opioides foram capazes de reduzir o efeito antinociceptivo. A via NO/cGMP/KATP também interfere na atividade farmacológica do composto devido a diminuição do efeito antinociceptivo com a administração prévia de L-NAME, ODQ e glibenclamida. A administração prévia de atropina reverteu a antinocicepção, sugerindo a participação do sistema colinérgico na atividade do composto LS19. Possivelmente há envolvimento de receptores TRPV1 neuronais e não-neuronais no mecanismo de ação do composto, pois no teste de nocicepção induzido por capsaicina, o LS19 inibiu o tempo de lambedura e foi capaz de diminuir tanto a hiperalgesia quanto a concentração de citocinas pró-inflamatórias induzidas por capsaicina. A atividade antinociceptiva do composto não está relacionada a um déficit motor, de acordo com dados obtidos no teste de rotarod. Em relação a atividade anti-inflamatória, o composto LS19 demonstrou um efeito anti-edematogênico, foi capaz de reduzir a migração leucocitária e a produção de citocinas pró-inflamatórias (IL-1β e TNF-α) e aumentar a síntese da IL-10, uma citocina anti-inflamatória. Na avaliação in vitro de atividade COX, o LS19 demonstrou maior, porém discreta, seletividade para COX-2. No ensaio toxicológico realizado, o composto não provocou alterações agudas e subcrônicas, tanto a nível macro quanto microscópico. Conclui-se então que o composto LS19 apresenta atividade antinociceptiva através de sua ação sobre as vias colinérgica e NO/cGMP/KATP, além de atividade anti-inflamatória e antinociceptiva induzida por ação sobre a via vanilóide e citocinas.
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spelling Gonçalves, Gabriela MastrangeloMarinho, Bruno Guimarães077.077.277-38http://lattes.cnpq.br/2685794388394484Marinho, Bruno GuimarãesMalvar, David do CarmoCôrtes, Wellington da SilvaNascimento, Carlos Giovani de OliveiraSouza, Giovane Galdino de384.158.588-41http://lattes.cnpq.br/03000791483596742023-12-21T18:39:16Z2023-12-21T18:39:16Z2020-10-02GONÇALVES, Gabriela Mastrangelo. Avaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto híbrido cis-(±)-acetato de 4-cloro-6-(naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2-(2-(2,6-diclorofenilamino) fenila. 2020. 133 f. Tese (Doutorado em Ciências Fisiológicas) - Instituto de Ciências Biológicas e da Saúde, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, 2020.https://rima.ufrrj.br/jspui/handle/20.500.14407/9431A hibridação molecular é uma estratégia clássica de conjugação de estruturas de compostos bioativos distintos em uma única molécula, sendo uma alternativa eficaz de arquitetar racionalmente novos compostos que podem apresentar sinergismo e terapia de dupla ação farmacológica ou modulação de efeitos adversos. O objetivo deste estudo foi avaliar a atividade antinociceptiva e anti-inflamatória de um novo composto híbrido: cis - (±) - acetato de 4-cloro-6- (naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2- (2-(2,6-diclorofenilamino) fenila (LS19), obtido através da hibridização do composto [(±)-(2,4,6-Cis)-4-cloro-6-(naftaleno-1-il)-tetrahidro-2H-pirano-2-il] metanol (CAPIM e cols., 2012) com o anti-inflamatório não-esteroidal diclofenaco de sódio. O composto LS19 foi administrado por via oral em todos os modelos animais e de acordo com os resultados, possui atividade contra a nocicepção aguda observada nos modelos de contorções abdominais induzidas por ácido acético, teste de formalina e imersão da cauda em água quente. O mecanismo de ação do composto envolve o sistema opioide, já que antagonistas seletivos opioides foram capazes de reduzir o efeito antinociceptivo. A via NO/cGMP/KATP também interfere na atividade farmacológica do composto devido a diminuição do efeito antinociceptivo com a administração prévia de L-NAME, ODQ e glibenclamida. A administração prévia de atropina reverteu a antinocicepção, sugerindo a participação do sistema colinérgico na atividade do composto LS19. Possivelmente há envolvimento de receptores TRPV1 neuronais e não-neuronais no mecanismo de ação do composto, pois no teste de nocicepção induzido por capsaicina, o LS19 inibiu o tempo de lambedura e foi capaz de diminuir tanto a hiperalgesia quanto a concentração de citocinas pró-inflamatórias induzidas por capsaicina. A atividade antinociceptiva do composto não está relacionada a um déficit motor, de acordo com dados obtidos no teste de rotarod. Em relação a atividade anti-inflamatória, o composto LS19 demonstrou um efeito anti-edematogênico, foi capaz de reduzir a migração leucocitária e a produção de citocinas pró-inflamatórias (IL-1β e TNF-α) e aumentar a síntese da IL-10, uma citocina anti-inflamatória. Na avaliação in vitro de atividade COX, o LS19 demonstrou maior, porém discreta, seletividade para COX-2. No ensaio toxicológico realizado, o composto não provocou alterações agudas e subcrônicas, tanto a nível macro quanto microscópico. Conclui-se então que o composto LS19 apresenta atividade antinociceptiva através de sua ação sobre as vias colinérgica e NO/cGMP/KATP, além de atividade anti-inflamatória e antinociceptiva induzida por ação sobre a via vanilóide e citocinas.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorMolecular hybridization is a classic strategy of conjugating structures of distinct bioactive compounds in a single molecule, being an effective alternative to rationally architect new compounds that may present synergism and double pharmacological action therapy or modulation of adverse effects. The aim of this study was to evaluate the antinociceptive and anti-inflammatory activity of a new hybrid compound: cis - (±) - 4-chloro-6- (naphthalene-1-yl) -tetrahydro-2H-pyran-2-yl ) methyl 2- (2- (2,6-dichlorophenylamino) phenyl (LS19), obtained by hybridizing the compound [(±) -(2,4,6-cis) -4-chloro-6- (naphthalene-1 -il) -tetrahydro-2H-pyran-2-yl] methanol (CAPIM et al., 2012) with the non-steroidal anti-inflammatory drug sodium diclofenac.The compound LS19 was administered orally in all animal models and according to the results, it has activity against the acute nociception observed in the models of abdominal contortions induced by acetic acid, formalin test and immersion of the tail in hot water. The mechanism of action of the compound involves the opioid system, since selective opioid antagonists were able to reduce the antinociceptive effect. The NO/cGMP/KATP pathway also interferes in the pharmacological activity of the compound due to the decrease of the antinociceptive effect with the previous administration of L-NAME, ODQ and glibenclamide. The previous administration of atropine reversed antinociception, suggesting the participation of the cholinergic system in the activity of the compound LS19. Possibly there is involvement of neuronal and non-neuronal TRPV1 receptors in the mechanism of action of the compound, as in the nociception test induced by capsaicin, LS19 inhibited the licking time and was able to decrease both hyperalgesia and the concentration of pro-inflammatory cytokines induced by capsaicin. The antinociceptive activity of the compound is not related to a motor deficit, according to data obtained in the rotarod test. In relation to anti-inflammatory activity, the compound LS19 demonstrated an anti-edematogenic effect, was able to reduce leukocyte migration and the production of pro-inflammatory cytokines (IL-1β and TNF-α) and increase the synthesis of IL-10, an anti-inflammatory cytokine. In the in vitro assessment of COX activity, LS19 demonstrated greater, but discrete, selectivity for COX-2. In the toxicological test carried out, the compound did not cause acute and subchronic changes, both at the macro and microscopic level. It is concluded that the compound LS19 has antinociceptive activity through its action on the cholinergic and NO / cGMP / KATP pathways, in addition to anti-inflammatory and antinociceptive activity induced by action on the vanilloid pathway and cytokines.application/pdfporUniversidade Federal Rural do Rio de JaneiroPrograma de Pós-Graduação em Ciências FisiológicasUFRRJBrasilInstituto de Ciências Biológicas e da SaúdeNocicepçãoSistema opioideInflamaçãoNociceptionOpioid systemInflammationFarmacologiaAvaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto híbrido cis-(±)-acetato de 4-cloro-6-(naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2- (2-(2,6-diclorofenilamino) fenilaAntinociceptive and anti-inflammatory profile of hybrid compound: 4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl cis-(±) methyl 2-2-(2,6-dichlorophenylamino) phenyl)info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisAHMED, S; SULTANA, M; HASAN, M. M. 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dc.title.por.fl_str_mv Avaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto híbrido cis-(±)-acetato de 4-cloro-6-(naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2- (2-(2,6-diclorofenilamino) fenila
dc.title.alternative.eng.fl_str_mv Antinociceptive and anti-inflammatory profile of hybrid compound: 4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl cis-(±) methyl 2-2-(2,6-dichlorophenylamino) phenyl)
title Avaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto híbrido cis-(±)-acetato de 4-cloro-6-(naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2- (2-(2,6-diclorofenilamino) fenila
spellingShingle Avaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto híbrido cis-(±)-acetato de 4-cloro-6-(naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2- (2-(2,6-diclorofenilamino) fenila
Gonçalves, Gabriela Mastrangelo
Nocicepção
Sistema opioide
Inflamação
Nociception
Opioid system
Inflammation
Farmacologia
title_short Avaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto híbrido cis-(±)-acetato de 4-cloro-6-(naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2- (2-(2,6-diclorofenilamino) fenila
title_full Avaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto híbrido cis-(±)-acetato de 4-cloro-6-(naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2- (2-(2,6-diclorofenilamino) fenila
title_fullStr Avaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto híbrido cis-(±)-acetato de 4-cloro-6-(naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2- (2-(2,6-diclorofenilamino) fenila
title_full_unstemmed Avaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto híbrido cis-(±)-acetato de 4-cloro-6-(naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2- (2-(2,6-diclorofenilamino) fenila
title_sort Avaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto híbrido cis-(±)-acetato de 4-cloro-6-(naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2- (2-(2,6-diclorofenilamino) fenila
author Gonçalves, Gabriela Mastrangelo
author_facet Gonçalves, Gabriela Mastrangelo
author_role author
dc.contributor.author.fl_str_mv Gonçalves, Gabriela Mastrangelo
dc.contributor.advisor1.fl_str_mv Marinho, Bruno Guimarães
dc.contributor.advisor1ID.fl_str_mv 077.077.277-38
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/2685794388394484
dc.contributor.referee1.fl_str_mv Marinho, Bruno Guimarães
dc.contributor.referee2.fl_str_mv Malvar, David do Carmo
dc.contributor.referee3.fl_str_mv Côrtes, Wellington da Silva
dc.contributor.referee4.fl_str_mv Nascimento, Carlos Giovani de Oliveira
dc.contributor.referee5.fl_str_mv Souza, Giovane Galdino de
dc.contributor.authorID.fl_str_mv 384.158.588-41
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/0300079148359674
contributor_str_mv Marinho, Bruno Guimarães
Marinho, Bruno Guimarães
Malvar, David do Carmo
Côrtes, Wellington da Silva
Nascimento, Carlos Giovani de Oliveira
Souza, Giovane Galdino de
dc.subject.por.fl_str_mv Nocicepção
Sistema opioide
Inflamação
topic Nocicepção
Sistema opioide
Inflamação
Nociception
Opioid system
Inflammation
Farmacologia
dc.subject.eng.fl_str_mv Nociception
Opioid system
Inflammation
dc.subject.cnpq.fl_str_mv Farmacologia
description A hibridação molecular é uma estratégia clássica de conjugação de estruturas de compostos bioativos distintos em uma única molécula, sendo uma alternativa eficaz de arquitetar racionalmente novos compostos que podem apresentar sinergismo e terapia de dupla ação farmacológica ou modulação de efeitos adversos. O objetivo deste estudo foi avaliar a atividade antinociceptiva e anti-inflamatória de um novo composto híbrido: cis - (±) - acetato de 4-cloro-6- (naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2- (2-(2,6-diclorofenilamino) fenila (LS19), obtido através da hibridização do composto [(±)-(2,4,6-Cis)-4-cloro-6-(naftaleno-1-il)-tetrahidro-2H-pirano-2-il] metanol (CAPIM e cols., 2012) com o anti-inflamatório não-esteroidal diclofenaco de sódio. O composto LS19 foi administrado por via oral em todos os modelos animais e de acordo com os resultados, possui atividade contra a nocicepção aguda observada nos modelos de contorções abdominais induzidas por ácido acético, teste de formalina e imersão da cauda em água quente. O mecanismo de ação do composto envolve o sistema opioide, já que antagonistas seletivos opioides foram capazes de reduzir o efeito antinociceptivo. A via NO/cGMP/KATP também interfere na atividade farmacológica do composto devido a diminuição do efeito antinociceptivo com a administração prévia de L-NAME, ODQ e glibenclamida. A administração prévia de atropina reverteu a antinocicepção, sugerindo a participação do sistema colinérgico na atividade do composto LS19. Possivelmente há envolvimento de receptores TRPV1 neuronais e não-neuronais no mecanismo de ação do composto, pois no teste de nocicepção induzido por capsaicina, o LS19 inibiu o tempo de lambedura e foi capaz de diminuir tanto a hiperalgesia quanto a concentração de citocinas pró-inflamatórias induzidas por capsaicina. A atividade antinociceptiva do composto não está relacionada a um déficit motor, de acordo com dados obtidos no teste de rotarod. Em relação a atividade anti-inflamatória, o composto LS19 demonstrou um efeito anti-edematogênico, foi capaz de reduzir a migração leucocitária e a produção de citocinas pró-inflamatórias (IL-1β e TNF-α) e aumentar a síntese da IL-10, uma citocina anti-inflamatória. Na avaliação in vitro de atividade COX, o LS19 demonstrou maior, porém discreta, seletividade para COX-2. No ensaio toxicológico realizado, o composto não provocou alterações agudas e subcrônicas, tanto a nível macro quanto microscópico. Conclui-se então que o composto LS19 apresenta atividade antinociceptiva através de sua ação sobre as vias colinérgica e NO/cGMP/KATP, além de atividade anti-inflamatória e antinociceptiva induzida por ação sobre a via vanilóide e citocinas.
publishDate 2020
dc.date.issued.fl_str_mv 2020-10-02
dc.date.accessioned.fl_str_mv 2023-12-21T18:39:16Z
dc.date.available.fl_str_mv 2023-12-21T18:39:16Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
status_str publishedVersion
dc.identifier.citation.fl_str_mv GONÇALVES, Gabriela Mastrangelo. Avaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto híbrido cis-(±)-acetato de 4-cloro-6-(naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2-(2-(2,6-diclorofenilamino) fenila. 2020. 133 f. Tese (Doutorado em Ciências Fisiológicas) - Instituto de Ciências Biológicas e da Saúde, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, 2020.
dc.identifier.uri.fl_str_mv https://rima.ufrrj.br/jspui/handle/20.500.14407/9431
identifier_str_mv GONÇALVES, Gabriela Mastrangelo. Avaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto híbrido cis-(±)-acetato de 4-cloro-6-(naftaleno-1-il)-tetraidro-2H-pirano-2-il) metil 2-(2-(2,6-diclorofenilamino) fenila. 2020. 133 f. Tese (Doutorado em Ciências Fisiológicas) - Instituto de Ciências Biológicas e da Saúde, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, 2020.
url https://rima.ufrrj.br/jspui/handle/20.500.14407/9431
dc.language.iso.fl_str_mv por
language por
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