Identification of Spiro[chromene-2,4'-piperidine]s as Potent, Selective, and G_q-Biased 5-HT_2C Receptor Partial Agonists

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.