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

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.