Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, New York 10065, United States.
Tri-Institutional Therapeutics Discovery Institute, 413 E. 69th Street, New York, New York 10021, United States.
ACS Chem Neurosci. 2022 Jul 6;13(13):1849-1856. doi: 10.1021/acschemneuro.2c00258. Epub 2022 Jun 23.
The kappa agonist structure-activity relationship around the novel, pyrrolidinyl substituted pyranopiperazine scaffold was developed. More specifically, the dichloroPhenylAcetamide-Pyrrolidinyl-PyranoPiperazine (PAPPP) core A was the focus of our work. The modulation of kappa receptor potency/G-protein activation and arrestin recruitment with respect to changes of the piperazine R group in A was demonstrated. Reduced β-arrestin recruitment and differential G-protein bias were observed for select analogues. To better understand the subtlety in receptor signaling, analogues were profiled as the resolved enantiomers. To determine target engagement, a subset of compounds was tested in mice for stimulation of serum prolactin, a neuroendocrine biomarker of KOR-agonist effects. Additional characterization included measurement of potential unwanted effects of kappa receptor activation such as sedation. These studies demonstrate a novel kappa receptor agonist scaffold with potential for G-protein signaling bias to probe pharmacology.
围绕新型吡咯烷取代吡喃哌啶骨架，对 κ 激动剂的结构-活性关系进行了研究。更具体地说，二氯苯基乙酰胺-吡咯烷基-吡喃哌啶（PAPPP）核心 A 是我们工作的重点。研究了哌嗪 R 基团变化对 κ 受体效力/G 蛋白激活和 arrestin 募集的调节。对于某些类似物，观察到 β-arrestin 募集减少和 G 蛋白偏析的差异。为了更好地了解受体信号的细微差别，将类似物作为解析对映体进行了分析。为了确定靶标结合，选择了一组化合物在小鼠中进行测试，以刺激血清催乳素，这是 KOR 激动剂作用的神经内分泌生物标志物。其他特征包括测量 κ 受体激活的潜在不良影响，如镇静。这些研究证明了一种新型 κ 受体激动剂骨架，具有 G 蛋白信号偏析的潜力，可用于研究药理学。
