Avaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto (±)-4-cloro-6-(naftaleno-1-il)-tetrahidro-2h-pirano-2-il-metanol

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 (μ, δ and κ) 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-α 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 κ-like receptors) and nitrergic in its mechanism of action. It has also showed an anti-inflammatory activity, with inhibition of leukocyte migration, TNF-α production and selective inhibitory activity on COX-2.