Abstract
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(2C)R) 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(2C)R selective agonists. Among this new series, the 7-chloro analogue 8 was identified as the most potent and selective 5-HT(2C)R partial agonist (E(max) = 71.09%) with an EC(50) value of 121.5 nM and no observed activity toward 5-HT(2A)R or 5-HT(2B)R. 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(2C)R partial agonists as useful pharmacological tool compounds or potential drug candidates.