Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom.
ACS Chem Neurosci. 2020 Dec 16;11(24):4270-4279. doi: 10.1021/acschemneuro.0c00540. Epub 2020 Nov 16.
Designer receptors exclusively activated by designer drugs (DREADDs) have been successfully employed to activate signaling pathways associated with specific muscarinic acetylcholine receptor (mAChR) subtypes. The M DREADD mAChR displays minimal responsiveness to the endogenous agonist acetylcholine (ACh) but responds to clozapine--oxide (CNO), an otherwise pharmacologically inert ligand. We have previously shown that benzyl quinolone carboxylic acid (BQCA), an M mAChR positive allosteric modulator (PAM), can rescue ACh responsiveness at these receptors. However, whether this effect is chemotype specific or applies to next-generation M PAMs with distinct scaffolds is unknown. Here, we reveal that new M PAMs restore ACh function at the M DREADD while modulating ACh binding at the M wild-type mAChR. Importantly, we demonstrate that the modulation of ACh function by M PAMs is translated using transgenic M DREADD mice. Our data provide important insights into mechanisms that define allosteric ligand modulation of agonist affinity vs efficacy and how these effects play out in the regulation of responses.
设计受体仅被设计药物（DREADD）激活，已成功用于激活与特定毒蕈碱乙酰胆碱受体（mAChR）亚型相关的信号通路。M DREADD mAChR 对内源性激动剂乙酰胆碱（ACh）的反应性极小，但对氯氮平 - 氧化物（CNO）有反应，CNO 是一种在药理学上无活性的配体。我们之前表明，苯并喹诺羧酸（BQCA），一种 M mAChR 正变构调节剂（PAM），可以恢复这些受体对 ACh 的反应性。然而，这种效应是否具有化学型特异性，或者是否适用于具有不同支架的下一代 M PAMs 尚不清楚。在这里，我们揭示了新的 M PAMs 可以在调节 M 野生型 mAChR 的 ACh 结合的同时，恢复 M DREADD 上的 ACh 功能。重要的是，我们证明了 M PAMs 对 ACh 功能的调节可以在转基因 M DREADD 小鼠中得到体现。我们的数据提供了对定义变构配体调节激动剂亲和力与效力的机制的重要见解，以及这些效应如何在调节反应中发挥作用。
