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在野生型小鼠中,DREADD 激动剂化合物 21 引起急性尿液流失

Bryce MacIver¹, Ali Wu¹, Warren G Hill¹

¹Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States.

Frontiers in pharmacology

|November 8, 2024

概括

化合物21 (C21) 是一种专用药物 (DREADD) 激素激活的设计受体,在小鼠中意外引起显著的利尿作用. 这突出了C21对脏和膀功能潜在的非目标影响.

科学领域:

药理学药理学是指药理学的学科.
腎臟病學 (nephrology) 是一種醫學專業.
分子生物学分子生物学

背景情况:

化学遗传学,特别是由设计药物 (DREADDs) 专门激活的设计受体,可以精确控制细胞功能.
化合物21 (C21) 是DREADDs的强有力的激动剂,但其可能与内源性G蛋白结合受体 (GPCRs) 的非目标结合需要研究.
了解内置对于调节功能至关重要,化学遗传学为研究提供了新的途径.

研究的目的:

从药理上描述化合物21 (C21) 对功能的影响.
调查C21的潜在非目标效应,特别是涉及脏和膀生理学的GPCRs.
评估C21对功能化学遗传研究的适用性.

主要方法:

将C21给麻醉和清醒的小鼠.
测量尿液输出和膜过率 (GFR).
排空点测试用于评估膀功能.
试管体内肌肉学,以评估C21对膀光滑肌收缩和M3受体对抗作用的影响.

主要成果:

给小鼠输注C21 (1.0 mg/kg) 导致尿量显著增加 (约4倍) 和GFR.
C21表现出急性利尿作用,在麻醉和清醒的动物模型中得到证实.
实验室研究表明,C21在微分子度下对抗M3受体,抑制膀光滑肌的收缩并增加排泄量.
C21在脏系统上表现出剂量依赖的非目标效应,作为GPCR抗剂.

结论:

化合物21 (C21) 对脏和膀系统具有显著的非目标作用,作为GPCR抗剂.
观察到的利尿和膀作用需要仔细考虑C21的剂量和化学遗传学研究中的潜在混影响.
需要进一步的表征才能充分理解C21的目标外活性对其用于研究功能的影响.

关键词:

反对主义的对立.化合物21 化合物21 化合物利尿症是一种利尿症.球膜过率是指球膜的过率顺滑肌肉的收缩性顺滑肌肉的收缩性

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