Avalia??o farmacol?gica das atividades antinociceptiva e anti-inflamat?ria do composto (?)-4-cloro-6-(naftaleno-1-il)-tetrahidro-2h-pirano-2-il-metanol

Several drugs in current use were discovered during experimental tests and by observing animals. When a new compound looks promising, it usually undergoes changes in its chemical structure in order to perfect its selectivity, potency and therapeutic efficacy. The aim of this study was to evaluate th...

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Publication Date:2016
Main Author: Gon?alves, Gabriela Mastrangelo lattes
Advisor: Marinho, Bruno Guimar?es lattes
Referee: Cortes, Wellington da Silva, Matheus, Maria Eline
Document type: Master thesis
Language:por
Published: Universidade Federal Rural do Rio de Janeiro
Program: Programa de P?s-Gradua??o em Ci?ncias Fisiol?gicas
Department: Instituto de Ci?ncias Biol?gicas e da Sa?de
Portuguese subjects:
English subjects:
Knowledgement areas:
Online Access:https://tede.ufrrj.br/jspui/handle/jspui/1425
Citation:Gon?alves, Gabriela Mastrangelo. Avalia??o farmacol?gica das atividades antinociceptiva e anti-inflamat?ria do composto (?)-4-cloro-6-(naftaleno-1-il)-tetrahidro-2h-pirano-2-il-metanol. 2016. [63 f.]. Disserta??o( PROGRAMA DE P?S-GRADUA??O EM CI?NCIAS FISIOL?GICAS) - Universidade Federal Rural do Rio de Janeiro, [Serop?dica-RJ]
Portuguese abstract:Diversos f?rmacos de uso corrente foram descobertos durante ensaios experimentais e mediante a observa??o em animais. Quando um novo composto parece promissor, geralmente este sofre altera??es em sua estrutura qu?mica a fim de aperfei?oar a sua seletividade, pot?ncia e efic?cia terap?utica. O objetivo deste estudo foi avaliar as atividades antinociceptiva e anti-inflamat?ria de um novo composto sint?tico (?)-4-cloro-6-(naftaleno-1-il)-tetrahidro-2h-pirano-2-il-metanol (CTHP) preparado a partir de um prot?tipo anterior, ?cido (?)-cis-(6-etil-tetrahidropirano-2-il) f?rmico. O composto CTHP foi avaliado em ensaios de indu??o de dor aguda. A administra??o oral do composto foi capaz de induzir atividade antinociceptiva nos modelos de contor??es abdominais induzidas por ?cido ac?tico, formalina (em ambas as fases) e retirada da cauda. Para elucida??o do mecanismo de a??o do composto, o modelo de retirada de cauda foi utilizado. Neste modelo foi realizada a administra??o pr?via de naloxona (antagonista opioide n?o-seletivo), em que foi observada a inibi??o do efeito produzido pelo composto. Assim, foi ent?o avaliada a participa??o seletiva de receptores opioides (?, ? e ?), atrav?s de administra??o pr?via de metilnaltrexona, naltrindol e nor-binaltorfimina, respectivamente, onde somente a nor-binaltorfimina foi capaz de reduzir o efeito antinociceptivo do composto. Para avaliar a poss?vel participa??o da via NO/GMPc/KATP, os animais foram pr?-tratados com N-nitro-arginina-L-metil ?ster (L-NAME), 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalina-1-ona (ODQ) (inibidor da guanilato ciclase sens?vel ao ?xido n?trico) e glibenclamida (bloqueador de canais de pot?ssio regulados por ATP), foi observado redu??o do efeito antinociceptivo com a administra??o pr?via de todos estes. No teste de indu??o de toler?ncia, tanto a morfina quanto o composto desenvolveram toler?ncia, por?m o composto de forma mais lenta e houve desenvolvimento de toler?ncia cruzada com a morfina. Para avaliar o envolvimento da via serotonin?rgica na atividade do composto, foi realizada a administra??o di?ria por 3 dias de 4-cloro-DL-fenilalanina (inibidor da enzima triptofano hidroxilase). Nenhuma altera??o no efeito antinociceptivo do composto foi observado, no que diz respeito ao envolvimento da via serotonin?rgica. J? o modelo de campo aberto foi utilizado para avaliar a possibilidade de interfer?ncia da performance motora sobre o efeito antinociceptivo, foi demonstrada aus?ncia desta interfer?ncia. Quanto ? atividade anti-inflamat?ria, o resultado no teste de edema de pata indica efeito antiedematog?nico do composto. Houve uma diminui??o na quantidade de leuc?citos totais, indicando que o composto foi capaz de reduzir a migra??o leucocit?ria na inflama??o existente na bolsa de ar subcut?neo. O composto tamb?m demonstrou atividade inibit?ria sobre a produ??o de TNF-? e inibi??o seletiva da enzima COX-2. Esses resultados indicam atividade antinociceptiva significativa do composto, sem evid?ncias de comprometimento motor. O composto CTHP demonstrou efeito antinociceptivo central, tendo este ?ltimo contribui??o dos sistemas opioide (seletivo para receptores do tipo ?) e nitr?rgico em seu mecanismo de a??o. E ainda, atividade anti-inflamat?ria, com inibi??o da migra??o leucocit?ria, de TNF-? e atividade inibit?ria seletiva sobre COX-2.
English abstract:Several drugs in current use were discovered during experimental tests and by observing animals. When a new compound looks promising, it usually undergoes changes in its chemical structure in order to perfect its selectivity, potency and therapeutic efficacy. The aim of this study was to evaluate the antinociceptive and anti-inflammatory activities of a new synthetic hybrid compound (?)-4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl-methanol (CTHP) prepared from a previous prototype acid, (?) - cis- (6-ethyl-tetrahydropyran-2-yl) Formic. The compound CTHP was evaluated in acute pain induction assays. Oral administration of the compound was able to induce antinociceptive activity in models of writhing induced by acetic acid, formalin (both stages) and tail flick. To elucidate the mechanism of action of the compound, the tail flick model was used. This model was perform by prior administration of naloxone (opioid antagonist non-selective), where we observed the inhibition of the effect produced by the compound. The selective involvement of opioid receptors (?, ? and ?) was then evaluated by prior administration of methylnaltrexone, naltrindol, and nor-binaltorphimine, respectively, where only nor-binaltorphimine was able to reduce the analgesic effect of the compound. To evaluate the possible role of the NO/cGMP/KATP, animals were pretreated with N-nitro-L-arginine methyl ester (L-NAME), 1H- [1,2,4 ] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) (inhibitor of guanylate cyclase sensitive to nitric oxide), and glibenclamide (blocker of the ATP-regulated potassium channels), where reduction was observed with the administration of analgesic effect prior to all of these. In the tolerance induction test, both morphine and compound developed tolerance, however the compound perform at a slower rate and developed cross-tolerance with morphine. To assess the involvement of serotonin pathway in the activity of the compound, daily administration for 3 days of 4-chloro-DL-phenylalanine (inhibitor of the enzyme tryptophan hydroxylase) was performed. No changes in the analgesic effect of the compound was noted, with regard to the involvement of serotonin pathway. The open field model was used to assess the possibility of interference from motor performance on the analgesic effect, which demonstrated absence of this interference. As for anti-inflammatory activity results in paw edema test indicate anti-oedematogenic effect of compound. There was a decrease in the number of total leukocytes, indicating that the compound was able to reduce existing inflammation in leukocyte migration in the air pouch model. The compound also demonstrated an inhibitory activity on TNF-? production and selective inhibition of COX-2 enzyme. These results indicate significant antinociceptive activity of the compound without evidence of motor impairment. The compound CTHP showed central analgesic effect, which has contribution of opioid systems (selective for the ?-like receptors) and nitrergic in its mechanism of action. It has also showed an anti-inflammatory activity, with inhibition of leukocyte migration, TNF-? production and selective inhibitory activity on COX-2.