Browsing by Author "Pacheco Paternina, Laura Cristina"
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Item Desarrollo de sulfonamidas como moduladores alostéricos positivos del receptor de glicina α3 fosforilado: una alternativa terapéutica potencial para el tratamiento del dolor crónico.(Universidad de Concepción, 2025) Pacheco Paternina, Laura Cristina; Ramírez Sánchez, David Mauricio; Moraga Cid, Gustavo Alonso; López Villa, Jhon JairoGlycine receptor modulation has emerged as a promising strategy for developing safer and more effective therapeutic alternatives for chronic pain treatment. This study evaluated the potential of sulfonamides containing tetrahydroquinoline rings as positive allosteric modulators (PAMs) of the glycine receptor α3 (GlyRα3). Phosphorylation of GlyRα3 at serine 346, mediated by protein kinase A (PKA), inhibits glycinergic currents and contributes to pain sensitization. To counteract this effect, sulfonamide derivatives with tetrahydroquinoline (THQs) rings for GlyRα3 were computationally designed and evaluated. Through molecular dynamics simulations and binding free energy (∆GBind) calculations, the most stable and high-affinity compounds were selected. Subsequently, electrophysiological recordings were used to assess their ability to modulate glycinergic currents in both wild-type GlyRα3 and its phosphomimetic mutant S346E. The results demonstrated that JL-02 and CO2-1 establish stable interactions with GlyRα3, exhibiting improved stability and specificity compared to AM-3607. Notably, CO2-1 significantly enhanced glycinergic currents in GlyRα3 S346E, positioning it as a promising candidate for novel pain therapies. This study provides a strong foundation for the development of allosteric modulators targeting phosphorylated GlyRα3, with potential applications in chronic pain treatment.