南佛罗里达大学Laura M. Bohn小组的论文发现了GTP选择性释放激动剂延长阿片类镇痛效果。该研究于2025年12月17日发表于国际一流学术期刊《自然》杂志上。

在这里，该课题组证明了一种激动剂可以显示出选择性亲和力的活性状态，倾向于释放GTP。具体来说，对于mu阿片受体，研究小组发现几种激动剂具有促进GTP释放而不是GTP结合的状态选择性亲和力。该课题组确定两种激动剂表现出明显的促进释放的偏好。在小鼠中，轻度有效剂量的释放偏好激动剂增强和延长吗啡和芬太尼的抗痛觉作用，但不增强芬太尼的呼吸和心脏作用。尽管这些观察结果仅限于热痛觉的简单测量，但它们可能指出了对这些激动剂的生理反应的两种方式。小组提出，激动剂的活性状态选择性可能决定受体GEF功能的首选方向，这可能会影响受体与下游效应器结合的动力学和选择性；这可能最终提供一种方法来解开多方面的药物诱导的生理反应。

据介绍，G蛋白偶联受体作为鸟嘌呤核苷酸交换因子（GEFs），通过将GDP交换为GTP1，促进异源三聚体G蛋白的激活。这个交换函数不是单向的。

附：英文原文

Title: GTP release-selective agonists prolong opioid analgesic efficacy

Author: Stahl, Edward L., Swanson, Matthew A., Dang, Vuong Q., Cameron, Michael D., Kennedy, Nicole M., Bannister, Thomas D., Bohn, Laura M.

Issue&Volume: 2025-12-17

Abstract: G-protein-coupled receptors act as guanine nucleotide exchange factors (GEFs) and facilitate the activation of heterotrimeric G proteins by exchanging GDP for GTP1. This exchange function is not unidirectional2. Here we demonstrate that an agonist can show selective affinity for an active state that prefers the release of GTP. Specifically, for the mu opioid receptor, we show that several agonists have state-selective affinities for promoting GTP release versus GTP binding. We identify two agonists that show a marked preference for promoting release. In mice, marginally efficacious doses of the release-preferring agonist enhance and prolong the antinociceptive effects of morphine and fentanyl without enhancing the respiratory and cardiac effects of fentanyl. Although these observations are limited to simple measures of thermal nociception, they may point to a way to bifurcate physiological responses to such agonists. We propose that the active-state selectivity of an agonist may determine the preferred direction of the receptor GEF function, which may affect the kinetics and selectivity of the engagement of the receptor with downstream effectors; this may ultimately present a means to disentangle multifaceted drug-induced physiological responses.

DOI: 10.1038/s41586-025-09880-5

Source: https://www.nature.com/articles/s41586-025-09880-5