Efeito antinociceptivo orofacial do derivado 2-amino-tiofeno 7CN03 e seus possíveis alvos de ação

Abstract

Orofacial pain impairs quality of life, and current therapies, limited in efficacy and associated with adverse effects, drive the search for new treatments. Thiophene derivatives exhibit remarkable therapeutic properties, including antinociceptive and anti-inflammatory activities, with recent studies demonstrating superior activity compared to commercial drugs, highlighting their relevance in the design of novel agents. This study investigated the antinociceptive effect of the thiophene derivative 2-[(4-diethylamino-benzylidene)-amino]-5,6,7,8-tetrahydro-4Hcyclohepta[ b]thiophene-3-carbonitrile (7CN03) and its possible mechanisms of action. In vivo tests were performed on male mice (n = 6 per group), with nociception induced by formalin, capsaicin, and glutamate one hour after treatment. Facial rubbing was used as a parameter to measure nociceptive behavior. In the in silico molecular docking test, the crystallographic structures of six targets involved in the pathophysiology of pain were selected and compared with agonists (opioid receptors) or antagonists (TRPV1, TRPA1, and NMDAR) for each of the targets. The Molegro Virtual Docker software was used to perform the molecular docking, and the redocking step was carried out based on the Root-Mean-Square Deviation. At different doses (1 mg/kg, 0.1 mg/kg, 0.01 mg/kg), 7CN03 exhibited significant action during the neurogenic phase of the formalin test, reducing nociceptive behavior by up to 56%. During the inflammatory phase, the 1 mg/kg dose exerted an antinociceptive effect, reducing nociceptive behavior by 32% (p < 0.05). In the glutamate test, 7CN03 blocked nociception by up to 90% (p < 0.001), and in the capsaicin test, it reduced nociceptive behavior by up to 74%. Molecular docking studies predicted higher binding affinity of 7CN03 for μ-opioid (-97.00 Kcal/mol), TRPV1 (-87.79 Kcal/mol), and NMDA (-104.86 Kcal/mol) receptors when compared with the cocrystallized ligands. The findings suggest that the evaluated thiophene derivative exhibits an orofacial antinociceptive effect, with a predicted mechanism of action involving opioid, transient vanilloid potential, and glutamatergic receptors.