Protease-activated receptor-2 (PAR2) is involved in inflammatory responses and pain, therefore representing a promising therapeutic target for the treatment of immune-mediated inflammatory diseases. However, as for other GPCRs, PAR2 can activate multiple signaling pathways and those involved in inflammatory responses remain poorly defined. Here, we describe a new selective and potent PAR2 inhibitor (I-287) that shows functional selectivity by acting as a negative allosteric regulator on Gα_q and Gα_12/13 activity and their downstream effectors, while having no effect on G_i/o signaling and βarrestin2 engagement. Such selective inhibition of only a subset of the pathways engaged by PAR2 was found to be sufficient to block inflammation in vivo. In addition to unraveling the PAR2 signaling pathways involved in the pro-inflammatory response, our study opens the path toward the development of new functionally selective drugs with reduced liabilities that could arise from blocking all the signaling activities controlled by the receptor.

蛋白酶激活受体2（PAR2）参与炎症反应和疼痛，因此代表了治疗免疫介导的炎症疾病的有希望的治疗靶标。但是，对于其他GPCR，PAR2可以激活多种信号通路，而与炎症反应有关的通路仍不清楚。在这里，我们描述了一种新的选择性和强效抑制剂PAR2（I-287），它显示功能选择性通过充当上Gα负性变构调节剂_q和Gα _12/13活性和其下游效应子，同时具有G上没有影响_{的i / o}信号传导和βarrestin2参与。发现仅选择性抑制PAR2参与的途径的子集足以阻断体内炎症。除了揭示促炎反应中涉及的PAR2信号传导途径外，我们的研究还为开发新的功能选择性药物提供了一条途径，该药物具有降低的耐药性，这可能是由于阻断受体控制的所有信号传导活性而引起的。