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Ajuste de la señalización GPCR sesgada para la ganancia fisiológica

Skylar Spangler¹, Michael R Bruchas²

¹Department of Anesthesiology, Division of Basic Research, Washington University School of Medicine, St. Louis, MO 63110, USA.

|November 18, 2017

Resumen

Los investigadores desarrollaron un nuevo método para diseñar analgésicos opiáceos más seguros. Este enfoque correlaciona el sesgo de señalización del receptor acoplado a la proteína G (GPCR) con la separación de dosis entre el alivio del dolor y la depresión respiratoria peligrosa en modelos animales.

Área de la Ciencia:

Farmacología
Química medicinal
La neurociencia

Sus antecedentes:

Los analgésicos opiáceos, como la morfina, son analgésicos eficaces, pero su utilidad clínica está limitada por la depresión respiratoria dependiente de la dosis.
La depresión respiratoria es un efecto adverso importante que limita la dosis de los analgésicos opioides, lo que requiere un ajuste cuidadoso de la dosis.
El desarrollo de analgésicos más seguros con índices terapéuticos mejorados sigue siendo una necesidad médica crítica no satisfecha.

Objetivo del estudio:

Presentar un método cuantitativo para diseñar nuevos ligandos con perfiles de seguridad mejorados.
Para correlacionar el sesgo de señalización del receptor acoplado a la proteína G (GPCR) con la separación entre efectos terapéuticos y adversos.
Establecer un marco para predecir y optimizar el índice terapéutico de los compuestos analgésicos.

Principales métodos:

Desarrollo de un enfoque cuantitativo de la relación estructura-actividad (QSAR) para el diseño de ligandos.
Evaluación del sesgo de señalización del GPCR mediante ensayos in vitro e in vivo en modelos animales.
Análisis de correlación entre las vías de señalización específicas y los efectos fisiológicos observados (analgesia y depresión respiratoria).

Principales resultados:

Se estableció un método cuantitativo para diseñar ligandos dirigidos a los GPCR.
El sesgo de señalización se correlacionó con éxito con la separación de dosis entre los efectos analgésicos y depresores respiratorios.
Los resultados proporcionan un modelo predictivo para optimizar el índice terapéutico de los analgésicos potenciales.

Conclusiones:

El método cuantitativo desarrollado permite el diseño racional de analgésicos opiáceos más seguros.
Comprender y manipular el sesgo de señalización GPCR es crucial para separar los efectos terapéuticos deseados de los eventos adversos.
Este enfoque es prometedor para el desarrollo de nuevos analgésicos con mejores perfiles de seguridad y eficacia.

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