Jiang Guangqian, Zhang Bingjie, Zhang Xiaoya, Chen Fan, Qin Wangzhi, Chen Jing-Lei, Tian Sheng, Shui Wenqing, Ye Na
Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
ACS Med Chem Lett. 2023 Dec 18;15(1):99-106. doi: 10.1021/acsmedchemlett.3c00454. eCollection 2024 Jan 11.
A series of spiropiperidines was designed and synthesized by structural modifications based on our previous lead compound and evaluated with cellular signaling assays for the discovery of 5-HT receptor (5-HTR) selective agonists with a G bias. Structure-activity relationship (SAR) studies of spiropiperidines uncovered spiro[chromene-2,4'-piperidine]s as a novel chemotype of 5-HTR selective agonists. Among this new series, the 7-chloro analogue was identified as the most potent and selective 5-HTR partial agonist ( = 71.09%) with an EC value of 121.5 nM and no observed activity toward 5-HTR or 5-HTR. Moreover, compound exhibited no recruitment activity for β-arrestin and showed low inhibition of hERG at 10 μM. These findings may pave the way to develop more potent G-biased 5-HTR partial agonists as useful pharmacological tool compounds or potential drug candidates.
基于我们之前的先导化合物，通过结构修饰设计并合成了一系列螺哌啶，并通过细胞信号测定法进行评估，以发现具有G偏向性的5-羟色胺受体（5-HTR）选择性激动剂。螺哌啶的构效关系（SAR）研究发现螺[色烯-2,4'-哌啶]作为5-HTR选择性激动剂的一种新型化学类型。在这个新系列中，7-氯类似物被确定为最有效和选择性的5-HTR部分激动剂（内在活性=71.09%），EC值为121.5 nM，对5-HTR或5-HTR未观察到活性。此外，化合物对β-抑制蛋白没有募集活性，在10μM时对hERG的抑制作用较低。这些发现可能为开发更有效的G偏向性5-HTR部分激动剂作为有用的药理学工具化合物或潜在药物候选物铺平道路。
