Referenced in: none

Automatically associated channels: TRP , TRPV , TRPV1

Title: A novel, potent, oral active and safe antinociceptive pyrazole targeting kappa opioid receptors.

Authors: Gabriela Trevisan, Mateus F Rossato, Cristiani I B Walker, Sara M Oliveira, Fernanda Rosa, Raquel Tonello, Cássia R Silva, Pablo Machado, Aline A Boligon, Marcos A P Martins, Nilo Zanatta, Hélio G Bonacorso, Margareth L Athayde, Maribel A Rubin, João B Calixto, Juliano Ferreira

Journal, date & volume: Neuropharmacology, 2013 Oct , 73, 261-73

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23791558

Abstract
Pyrazole compounds are an intriguing class of compounds with potential analgesic activity; however, their mechanism of action remains unknown. Thus, the goal of this study was to explore the antinociceptive potential, safety and mechanism of action of novel 1-pyrazole methyl ester derivatives, which were designed by molecular simplification, using in vivo and in vitro methods in mice. First, tree 1-pyrazole methyl ester derivatives (DMPE, MPFE, and MPCIE) were tested in the capsaicin test and all presented antinociceptive effect; however the MPClE (methyl 5-trichloromethyl-3-methyl-1H-pyrazole-1-carboxylate) was the most effective. Thus, we selected this compound to assess the effects and mechanisms in subsequent pain models. MPCIE produced antinociception when administered by oral, intraperitoneal, intrathecal and intraplantar routes and was effective in the capsaicin and the acetic acid-induced nociception tests. Moreover, this compound reduced the hyperalgesia in diverse clinically-relevant pain models, including postoperative, inflammatory, and neuropathic nociception in mice. The antinociception produced by orally administered MPClE was mediated by κ-opioid receptors, since these effects were prevented by systemically pre-treatment with naloxone and the κ-opioid receptor antagonist nor-binaltorphimine. Moreover, MPCIE prevented binding of the κ-opioid ligand [(3)H]-CI-977 in vitro (IC₅₀ of 0.68 (0.32-1.4) μM), but not the TRPV1 ([(3)H]-resiniferatoxin) or the α₂-adrenoreceptor ([(3)H]-idazoxan) binding. Regarding the drug-induced side effects, oral administration of MPClE did not produce sedation, constipation or motor impairment at its active dose. In addition, MPCIE was readily absorbed after oral administration. Taken together, these results demonstrate that MPClE is a novel, potent, orally active and safe analgesic drug that targets κ-opioid receptors.