Antinociceptive effects of new pyrazoles compounds mediated by the ASIC-1? channel, TRPV-1 and ?MOR receptors - 09/06/19

pages | 12 |
Iconographies | 8 |
Vidéos | 0 |
Autres | 0 |
Graphical abstract |
Abstract |
Pyrazoles are potent medicinal scaffolds and exhibit a wide spectrum of biological activities, such as analgesic, anti-inflammatory and antipyretic. In this paper we report on research we have performed with the aim of continuing the biological evaluation of the regio-isomeric pyrazole compounds, LQFM-020 (fluorine, para position), LQFM-021 (fluorine, meta position), and LQFM-039 (fluorine, ortho position) in models of pain induced by acidified saline, capsaicin, and formalin. We also investigated the mechanisms of action of these compounds via electrophysiological analyses using the two-electrode voltage-clamp technique and heterologous expression in Xenopus laevis oocytes. This enabled us to study different potassium channel subtypes: the ASIC-1α channel, TRPV-1, and μMOR receptors. Our results indicate that LQFM-020, LQFM-021, and LQFM-039 (15, 30 or 60 mg.kg−1) compounds inhibited the nociceptive response induced by acidified saline in a dose-dependent manner. The dose of 30 mg.kg−1 inhibited the nociceptive response induced by capsaicin by 53.3%, 51.4%, and 52.1%, respectively. In addition, we found that naloxone reverses the antinociceptive effect produced by the compounds in both phases of the formalin test. In electrophysiological analyses, we observed that the LQFM-020, LQFM-021, and LQFM-039 compounds did not modulate voltage-gated K + channel subtypes. In contrast, all the compounds tested inhibited the ASIC-1α channel at pH 4.5, with IC50-values of 96.1, 91.6, and 235.2 μM, respectively. All compounds also inhibited the TRPV-1 channel with IC50-values of 139.1, 212.5, and 159.1 μM, respectively. In contrast to the ASIC-1α and TRPV-1 targets, all compounds showed agonist activity on the μMOR receptor with an EC50-value of 117.4, 98.9, and 86.3 μM, respectively. We thus conclude that the ASIC-1α, TRPV-1, and μMOR channels are targets that are directly involved in the antinociceptive effect of LQFM-020, LQFM-021, and LQFM-039. Furthermore, the modifications of the fluorine positions in the phenyl analogs do not change the analgesic effect. However, LQFM-039 showed lower interaction with ASIC-1α channel.
Le texte complet de cet article est disponible en PDF.Abbreviations : ASIC-1α, TRPV-1, μMOR, NSAIDs, NO, cGMP, KATP channel, Kv, Shaker IR, hERG, HEPES, GIRK1/GIRK2, SEM
Keywords : Analgesic, Electrophysiology, Ion channels, Pain, Pyrazole compounds, Receptor, Xenopus laevis
Plan
Vol 115
Article 108915- juillet 2019 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’achat d’article à l’unité est indisponible à l’heure actuelle.
Déjà abonné à cette revue ?