HBK-17, a 5-HT_1A receptor ligand with anxiolytic-like activity, preferentially activates ß-arrestin signaling

The takeaway

HBK-17, a novel serotonin receptor ligand, shows anxiolytic-like effects in mice but primarily activates the β-arrestin pathway, offering a different mechanism compared to traditional anxiolytics.

The science

HBK-17 exhibits high affinity for 5-HT_1A receptors and has moderate interactions with D₂, while showing weak affinity for 5-HT7 receptors. In behavioral tests like the four-plate and elevated plus maze, it increased exploratory behavior without influencing pain sensitivity or movement, confirming its anxiolytic-like properties. This effect was absent after serotonin depletion or blockade of 5-HT_1A receptors, highlighting the role of the serotonergic system. Cellular assays indicated that HBK-17 primarily promotes β-arrestin recruitment at 5-HT_1A receptors rather than activating calcium or cAMP pathways. Pharmacokinetic data showed rapid absorption, brain access, and moderate bioavailability.

Why it matters

By biasing signaling through β-arrestin at 5-HT_1A receptors, HBK-17 may provide anti-anxiety benefits with fewer side effects, highlighting biased agonism as a promising approach for next-generation anxiolytics.

Original article

https://doi.org/10.1371/journal.pone.0142499