Identification of Spiro[chromene-2,4′-piperidine]s as Potent, Selective, and Gq-Biased 5-HT2C Receptor Partial Agonists,ACS Medicinal Chemistry Letters

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Identification of Spiro[chromene-2,4′-piperidine]s as Potent, Selective, and Gq-Biased 5-HT2C Receptor Partial Agonists
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2023-12-18 , DOI: 10.1021/acsmedchemlett.3c00454
Guangqian Jiang ₁ , Bingjie Zhang _{2,

3} , Xiaoya Zhang ₁ , Fan Chen ₁ , Wangzhi Qin ₁ , Jing-Lei Chen ₁ , Sheng Tian ₁ , Wenqing Shui _{2,

3} , Na Ye ₁

Affiliation

A series of spiropiperidines was designed and synthesized by structural modifications based on our previous lead compound 1 and evaluated with cellular signaling assays for the discovery of 5-HT_2C receptor (5-HT_2CR) selective agonists with a G_q bias. Structure–activity relationship (SAR) studies of spiropiperidines uncovered spiro[chromene-2,4′-piperidine]s as a novel chemotype of 5-HT_2CR selective agonists. Among this new series, the 7-chloro analogue 8 was identified as the most potent and selective 5-HT_2CR partial agonist (E_max = 71.09%) with an EC₅₀ value of 121.5 nM and no observed activity toward 5-HT_2AR or 5-HT_2BR. Moreover, compound 8 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_q-biased 5-HT_2CR partial agonists as useful pharmacological tool compounds or potential drug candidates.

中文翻译：

鉴定螺[色烯-2,4'-哌啶]作为有效、选择性和 Gq 偏向的 5-HT2C 受体部分激动剂

基于我们之前的先导化合物1，通过结构修饰设计和合成了一系列螺哌啶，并通过细胞信号转导测定进行评估，以发现具有 G _q偏向的 5-HT _2C受体 (5-HT _2C R) 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]是一种新型 5-HT _2C R 选择性激动剂化学型。在这个新系列中，7-氯类似物8被确定为最有效和最具选择性的 5-HT _2C R 部分激动剂 ( E _max = 71.09%)，EC ₅₀值为 121.5 nM，并且没有观察到对 5-HT _2A的活性R 或 5-HT _2B R。此外，化合物8对 β-arrestin 没有表现出募集活性，并且在 10 μM 时表现出对 hERG 的低抑制作用。这些发现可能为开发更有效的 G _q偏向 5-HT _2C R 部分激动剂作为有用的药理学工具化合物或潜在的候选药物铺平道路。

更新日期：2023-12-18

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