Desarrollo de sulfonamidas como moduladores alostéricos positivos del receptor de glicina α3 fosforilado: una alternativa terapéutica potencial para el tratamiento del dolor crónico.
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Date
2025
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Publisher
Universidad de Concepción
Abstract
La modulación de los receptores de glicina ha surgido como una estrategia prometedora para el desarrollo de alternativas terapéuticas más seguras y efectivas para tratar el dolor crónico. En este estudio, se evaluó el potencial de sulfonamidas con anillos de tetrahidroquinolina (THQ) fusionadas como moduladores alostéricos positivos (MAPs) del receptor de glicina α3 (GlyRα3). La fosforilación de GlyRα3 en la serina 346, mediada por la proteína quinasa A (PKA), inhibe las corrientes glicinérgicas y contribuye a la sensibilización al dolor. Para revertir este efecto, se diseñaron y evaluaron computacionalmente derivados de sulfonamidas con anillos de THQ. Mediante simulaciones de dinámica molecular y cálculos de energía libre de unión (∆GBind), se seleccionaron los compuestos con mayor estabilidad y afinidad por GlyRα3. Posteriormente, registros electrofisiológicos permitieron evaluar su capacidad para modular las corrientes glicinérgicas en GlyRα3 wild-type y en su mutante fosfomimética S346E. Los resultados mostraron que JL-02 y CO2-1 presentan interacciones estables con el sitio alostérico de GlyRα3, con mejoras en estabilidad y especificidad respecto a AM-3607. En particular, CO2-1 exhibió una potenciación significativa de las corrientes glicinérgicas en GlyRα3 S346E, consolidándolo como un candidato prometedor para el desarrollo de nuevas terapias. Este estudio proporciona una base sólida para el desarrollo de nuevos moduladores alostéricos dirigidos a GlyRα3 fosforilado con potencial aplicación en el tratamiento del dolor crónico.
Glycine 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.
Glycine 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.
Description
Tesis presentada para optar al grado de Magíster en Bioquímica y Bioinformática
Keywords
Sulfonamidas, Farmacología, Dolor crónico