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Reconocimiento molecular de la morfina y el fentanilo por el receptor humano de μ-opioides

Youwen Zhuang¹, Yue Wang², Bingqing He³

¹The CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

|November 11, 2022

Resumen

La morfina y el fentanilo se unen al receptor mu-opioide (μOR) de manera diferente. Comprender estas estructuras ayuda a diseñar medicamentos más seguros y efectivos para aliviar el dolor al dirigirse a vías de señalización específicas.

Área de la Ciencia:

Biología estructural
Farmacología
La neurociencia

Sus antecedentes:

Los analgésicos opioides como la morfina y el fentanilo activan el receptor mu-opioide (μOR).
La activación de μOR involucra a las vías de señalización de la proteína G y la arrestina, lo que conduce tanto al alivio del dolor como a los efectos secundarios.

Objetivo del estudio:

Para aclarar la base estructural de la unión de la morfina y el fentanilo a la μOR humana.
Investigar los modos de unión diferenciales de varios agonistas μOR.
Para entender cómo las interacciones de ligandos dictan el sesgo de la vía de señalización.

Principales métodos:

Determinadas estructuras de microscopía criolectrónica de μOR humano complejo con proteínas G y varios ligandos.
Realizó mutagenesis dirigida al sitio para sondear el papel de las interfaces receptoras específicas.
Se evaluó la detención del reclutamiento y la señalización de la proteína G en respuesta a la estimulación del ligando.

Principales resultados:

Se revelaron modos de unión distintos para la morfina y el fentanilo en la μOR.
Se identificaron interacciones preferenciales TM3 para TRV130, PZM21 y SR17018, en contraste con las interacciones duales TM3 y TM6/7 para la morfina y el fentanilo.
Se demostró que las mutaciones de la interfaz TM6 / 7 eliminan el reclutamiento de arrestina por morfina y fentanilo, y los ligandos dirigidos a esto reducen el sesgo de arrestina.

Conclusiones:

Se proporcionan información estructural sobre el reconocimiento del fentanilo por μOR.
Se pueden emplear estrategias de diseño de ligandos para favorecer la señalización de proteínas G sobre las vías de arrestina.
Estos hallazgos pueden orientar el desarrollo de analgésicos de próxima generación con perfiles de seguridad mejorados.

Palabras clave:

analgésico señalización sesgada de la proteína G Crio-EM diseño de fármacos Fentanilo y sus derivados Derivados del fentanilo La morfina también.receptores de opiáceos agonismo parcial En el caso de los

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