Derivados pirazolínicos inéditos causam antinocicepção em camundongos no teste da formalina
Autor(a) principal: | |
---|---|
Data de Publicação: | 2004 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Repositório Institucional Manancial UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/11162 |
Resumo: | The discovery of pyrazole derivatives dates back to 1884, when the German chemist Ludwig Knorr attempted to synthesize quinoline derivatives with antipyretic activity and accidentally obtained antipyrine, a pyrazolinone, which has analgesic, antipyretic and antirheumatic activity. Since then, new pyrazole compounds, like phenylbutazone and dipyrone, were discovered. Dipyrone, probably the most widely studied pyrazole derivative, present analgesic, antipyretic and few antiinflammatory activities. The mechanism of action of pyrazole compounds seems to involve the central and peripheral inhibition of cyclooxygenase, a key enzyme in the synthesis of prostaglandin. In this work we studied the antinociceptive and antiinflammatory effects of a novel pyrazole-derived compounds: 4-methyl-5-hydroxy-5-trifloromethyl-4,5-diidro-1H-1-pyrazolcarboxyamide (NF0) and its related compound 3- methyl-5-hydroxy-5-trifloromethyl-4,5-diidro-1H-1-pyrazolcarboxyamide (NF2). The antinociceptive potential was assessed using abdominal writhing, hot plate and formalin tests in adult mice. Antiinflammatory activity was assessed by paw plethysmometry in adult rats using the carrageenin-induced paw edema test. Subcutaneous administration of NF0 (30, 100, 300 and 1000 μmol/kg) decreased time spent licking or biting the injected paw in the neurogenic phase of the formalin test. However, only 300 and 1000 μmol/kg NF0 decreased licking time in the inflammatory phase of the formalin test. On the other hand, subcutaneous administration of NF2 had no effect on licking time during the neurogenic phase, but decreased licking time in inflammatory phase of the formalin test at dose of 1000 μmol/kg. Naloxone (2,75 μmol/kg) pre-administration did not prevent NF0 and NF2-induced antinociception, suggesting that opioid mechanisms may not underlie such effects. NF0 and NF2 were devoid of antiinflammatory activity in the paw edema test in rats, and had no effect on the spontaneous locomotor activity and motor performance of mice in the rotarod test. These results suggest that NF0 induces antinociception in the neurogenic and inflammatory phases of the formalin test, while NF2 causes antinociception only inflammatory phase. Interestingly, the only difference between these compounds is the position of a methyl group in the pyrazole ring. In NF0, the methyl group is placed at position 4 of the pyrazole ring, while NF2 has such a methyl group positioned at the position 3. These results suggest an important structure-activity relationship for the antinociceptive effect these compounds. |
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2017-04-262017-04-262004-07-29SAUZEM, Patricia Dutra. New pirazole derivatives induced antinociception in mice in the formalin test. 2004. 110 f. Dissertação (Mestrado em Bioquímica) - Universidade Federal de Santa Maria, Santa Maria, 2004.http://repositorio.ufsm.br/handle/1/11162The discovery of pyrazole derivatives dates back to 1884, when the German chemist Ludwig Knorr attempted to synthesize quinoline derivatives with antipyretic activity and accidentally obtained antipyrine, a pyrazolinone, which has analgesic, antipyretic and antirheumatic activity. Since then, new pyrazole compounds, like phenylbutazone and dipyrone, were discovered. Dipyrone, probably the most widely studied pyrazole derivative, present analgesic, antipyretic and few antiinflammatory activities. The mechanism of action of pyrazole compounds seems to involve the central and peripheral inhibition of cyclooxygenase, a key enzyme in the synthesis of prostaglandin. In this work we studied the antinociceptive and antiinflammatory effects of a novel pyrazole-derived compounds: 4-methyl-5-hydroxy-5-trifloromethyl-4,5-diidro-1H-1-pyrazolcarboxyamide (NF0) and its related compound 3- methyl-5-hydroxy-5-trifloromethyl-4,5-diidro-1H-1-pyrazolcarboxyamide (NF2). The antinociceptive potential was assessed using abdominal writhing, hot plate and formalin tests in adult mice. Antiinflammatory activity was assessed by paw plethysmometry in adult rats using the carrageenin-induced paw edema test. Subcutaneous administration of NF0 (30, 100, 300 and 1000 μmol/kg) decreased time spent licking or biting the injected paw in the neurogenic phase of the formalin test. However, only 300 and 1000 μmol/kg NF0 decreased licking time in the inflammatory phase of the formalin test. On the other hand, subcutaneous administration of NF2 had no effect on licking time during the neurogenic phase, but decreased licking time in inflammatory phase of the formalin test at dose of 1000 μmol/kg. Naloxone (2,75 μmol/kg) pre-administration did not prevent NF0 and NF2-induced antinociception, suggesting that opioid mechanisms may not underlie such effects. NF0 and NF2 were devoid of antiinflammatory activity in the paw edema test in rats, and had no effect on the spontaneous locomotor activity and motor performance of mice in the rotarod test. These results suggest that NF0 induces antinociception in the neurogenic and inflammatory phases of the formalin test, while NF2 causes antinociception only inflammatory phase. Interestingly, the only difference between these compounds is the position of a methyl group in the pyrazole ring. In NF0, the methyl group is placed at position 4 of the pyrazole ring, while NF2 has such a methyl group positioned at the position 3. These results suggest an important structure-activity relationship for the antinociceptive effect these compounds.Os derivados pirazolínicos foram descobertos por volta de 1884 pelo químico alemão Ludwig Knorr, quando ele tentava sintetizar derivados de quinolina com atividade antipirética e, acidentalmente, obteve a antipirina, uma pirazolona com atividade analgésica, antipirética e anti-reumática. Desde então, novos compostos pirazolínicos como a fenilbutazona e a dipirona foram descobertos. O derivado pirazolínico mais estudado até o momento é a dipirona, que apresenta atividade antipirética, analgésica e pouca atividade antiinflamatória. O mecanismo de ação proposto para os compostos pirazolínicos é a inibição da síntese de prostaglandinas, tanto central quanto perifericamente. Nesse trabalho avaliou-se o potencial antinociceptivo e antiedematogênico de dois derivados pirazolínicos inéditos: 4-metil-5-hidróxi-5-trifluormetil-4,5-diidro-1H-1-pirazolcarboxamida (NF0) e seu análogo 3- metil-5-hidróxi-5-trifluormetil-4,5-diidro-1H-1-pirazolcarboxamida (NF2). O potencial antinociceptivo foi avaliado nos testes de contorções abdominais induzidas por ácido acético, placa quente, e formalina, em camundongos. A atividade antiedematogênica foi avaliada em ratos, pelo teste de edema de pata induzido por carragenina. Também foi avaliado o efeito dessas drogas sobre a atividade locomotora e exploratória de camundongos. A administração subcutânea do NF0 (30, 100, 300 e 1000 μmol/kg) induziu diminuição do comportamento de lamber a pata na fase neurogênica do teste de formalina, enquanto que somente as duas maiores doses foram capazes de inibir a nocicepção na fase inflamatória desse teste. Por outro lado, o NF2 não apresentou ação na fase neurogênica e foi capaz de inibir o comportamento de lamber a pata, apenas na dose de 1000 μmol/kg, na fase inflamatória. A pré-administração de naloxona (2,75 μmol/kg) não preveniu a antincicepção induzida pelo NF0 e pelo NF2. O NF0 e o NF2 não tiveram efeito antiedematogênico no teste de edema de pata induzido por carragenina, quando administrados numa dose de 200 μmol/kg. Esses compostos, também, não alteraram a atividade motora dos camundongos no teste do cilindro giratório e não modificaram o comportamento dos animais no campo aberto. Esses resultados sugerem que o NF0 induz antinocicepção nas fases neurogênica e inflamatória no teste da formalina, enquanto que o NF2 somente apresenta efeito na fase inflamatória, e que esse efeito não envolve mecanismos opióides. É importante ressaltar que a única diferença estrutural desses compostos reside na posição de um grupamento metila, que no NF0 encontra-se na posição 4 do anel pirazol e no NF2 está na posição 3 do anel, demonstrando uma importante relação estrutura-atividade no efeito antinociceptivo desses compostos.application/pdfporUniversidade Federal de Santa MariaPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaUFSMBRBioquímicaBioquímicaFarmáciaCompostos pirazolínicosMedicamentosDorCNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICADerivados pirazolínicos inéditos causam antinocicepção em camundongos no teste da formalinaNew pirazole derivatives induced antinociception in mice in the formalin testinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisRubin, Maribel Antonellohttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4794806H7Bonacorso, Helio Gauzehttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4788537E0http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4764634Z1Sauzem, Patricia Dutra20080000000240050050050017f72a93-232f-40b3-9c14-1b54b978789b8094411c-c0bb-4b7e-a2b3-aa07422baff8dbcce58b-96b0-4f45-a78d-ca6f339e038dinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional Manancial UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALPATRICIASAUZEN.pdfapplication/pdf550147http://repositorio.ufsm.br/bitstream/1/11162/1/PATRICIASAUZEN.pdfb723f54ea139dd27f7141139f8fd1c18MD51TEXTPATRICIASAUZEN.pdf.txtPATRICIASAUZEN.pdf.txtExtracted texttext/plain118434http://repositorio.ufsm.br/bitstream/1/11162/2/PATRICIASAUZEN.pdf.txt4c602533b997a18ad3a2187523ad3503MD52THUMBNAILPATRICIASAUZEN.pdf.jpgPATRICIASAUZEN.pdf.jpgIM Thumbnailimage/jpeg5528http://repositorio.ufsm.br/bitstream/1/11162/3/PATRICIASAUZEN.pdf.jpg4fbf5b761d8b69c695807ef284886968MD531/111622017-07-25 12:09:51.489oai:repositorio.ufsm.br:1/11162Repositório Institucionalhttp://repositorio.ufsm.br/PUBhttp://repositorio.ufsm.br/oai/requestouvidoria@ufsm.bropendoar:39132017-07-25T15:09:51Repositório Institucional Manancial UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.por.fl_str_mv |
Derivados pirazolínicos inéditos causam antinocicepção em camundongos no teste da formalina |
dc.title.alternative.eng.fl_str_mv |
New pirazole derivatives induced antinociception in mice in the formalin test |
title |
Derivados pirazolínicos inéditos causam antinocicepção em camundongos no teste da formalina |
spellingShingle |
Derivados pirazolínicos inéditos causam antinocicepção em camundongos no teste da formalina Sauzem, Patricia Dutra Bioquímica Farmácia Compostos pirazolínicos Medicamentos Dor CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
title_short |
Derivados pirazolínicos inéditos causam antinocicepção em camundongos no teste da formalina |
title_full |
Derivados pirazolínicos inéditos causam antinocicepção em camundongos no teste da formalina |
title_fullStr |
Derivados pirazolínicos inéditos causam antinocicepção em camundongos no teste da formalina |
title_full_unstemmed |
Derivados pirazolínicos inéditos causam antinocicepção em camundongos no teste da formalina |
title_sort |
Derivados pirazolínicos inéditos causam antinocicepção em camundongos no teste da formalina |
author |
Sauzem, Patricia Dutra |
author_facet |
Sauzem, Patricia Dutra |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Rubin, Maribel Antonello |
dc.contributor.advisor1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4794806H7 |
dc.contributor.referee1.fl_str_mv |
Bonacorso, Helio Gauze |
dc.contributor.referee1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4788537E0 |
dc.contributor.authorLattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4764634Z1 |
dc.contributor.author.fl_str_mv |
Sauzem, Patricia Dutra |
contributor_str_mv |
Rubin, Maribel Antonello Bonacorso, Helio Gauze |
dc.subject.por.fl_str_mv |
Bioquímica Farmácia Compostos pirazolínicos Medicamentos Dor |
topic |
Bioquímica Farmácia Compostos pirazolínicos Medicamentos Dor CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
description |
The discovery of pyrazole derivatives dates back to 1884, when the German chemist Ludwig Knorr attempted to synthesize quinoline derivatives with antipyretic activity and accidentally obtained antipyrine, a pyrazolinone, which has analgesic, antipyretic and antirheumatic activity. Since then, new pyrazole compounds, like phenylbutazone and dipyrone, were discovered. Dipyrone, probably the most widely studied pyrazole derivative, present analgesic, antipyretic and few antiinflammatory activities. The mechanism of action of pyrazole compounds seems to involve the central and peripheral inhibition of cyclooxygenase, a key enzyme in the synthesis of prostaglandin. In this work we studied the antinociceptive and antiinflammatory effects of a novel pyrazole-derived compounds: 4-methyl-5-hydroxy-5-trifloromethyl-4,5-diidro-1H-1-pyrazolcarboxyamide (NF0) and its related compound 3- methyl-5-hydroxy-5-trifloromethyl-4,5-diidro-1H-1-pyrazolcarboxyamide (NF2). The antinociceptive potential was assessed using abdominal writhing, hot plate and formalin tests in adult mice. Antiinflammatory activity was assessed by paw plethysmometry in adult rats using the carrageenin-induced paw edema test. Subcutaneous administration of NF0 (30, 100, 300 and 1000 μmol/kg) decreased time spent licking or biting the injected paw in the neurogenic phase of the formalin test. However, only 300 and 1000 μmol/kg NF0 decreased licking time in the inflammatory phase of the formalin test. On the other hand, subcutaneous administration of NF2 had no effect on licking time during the neurogenic phase, but decreased licking time in inflammatory phase of the formalin test at dose of 1000 μmol/kg. Naloxone (2,75 μmol/kg) pre-administration did not prevent NF0 and NF2-induced antinociception, suggesting that opioid mechanisms may not underlie such effects. NF0 and NF2 were devoid of antiinflammatory activity in the paw edema test in rats, and had no effect on the spontaneous locomotor activity and motor performance of mice in the rotarod test. These results suggest that NF0 induces antinociception in the neurogenic and inflammatory phases of the formalin test, while NF2 causes antinociception only inflammatory phase. Interestingly, the only difference between these compounds is the position of a methyl group in the pyrazole ring. In NF0, the methyl group is placed at position 4 of the pyrazole ring, while NF2 has such a methyl group positioned at the position 3. These results suggest an important structure-activity relationship for the antinociceptive effect these compounds. |
publishDate |
2004 |
dc.date.issued.fl_str_mv |
2004-07-29 |
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2017-04-26 |
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2017-04-26 |
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SAUZEM, Patricia Dutra. New pirazole derivatives induced antinociception in mice in the formalin test. 2004. 110 f. Dissertação (Mestrado em Bioquímica) - Universidade Federal de Santa Maria, Santa Maria, 2004. |
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http://repositorio.ufsm.br/handle/1/11162 |
identifier_str_mv |
SAUZEM, Patricia Dutra. New pirazole derivatives induced antinociception in mice in the formalin test. 2004. 110 f. Dissertação (Mestrado em Bioquímica) - Universidade Federal de Santa Maria, Santa Maria, 2004. |
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