Antidepressant- and anxiolytic-like effects of new dual 5-HT_1A and 5-HT₇ antagonists in animal models

The takeaway

HBK-14 and HBK-15, which are dual antagonists of 5-HT_1A and 5-HT₇ receptors, demonstrate both antidepressant- and anxiolytic-like effects in rodents, indicating their potential as multi-target therapies for mood and anxiety disorders.

The science

HBK-14 and HBK-15 target serotonin receptors, mainly 5-HT_1A and 5-HT_7, which play key roles in mood and anxiety regulation. In behavioral tests, both compounds decreased immobility in the forced swim test, indicating antidepressant-like effects, with HBK-15 showing stronger results. They also enhanced exploratory behavior in anxiety models such as the four-plate test and elevated plus maze, where HBK-14 was more effective. These effects depended on serotonin signaling, as they vanished after serotonin depletion or blocking 5-HT_1A receptors. Besides serotonin, the compounds also showed affinity for adrenergic and dopaminergic receptors, indicating a multimodal profile. Importantly, neither impaired locomotor activity nor coordination was observed, suggesting a favorable safety margin.

Why it matters

By concurrently targeting serotonergic receptors linked to mood and anxiety regulation, HBK-14 and HBK-15 could address some limitations of existing single-target treatments.

Original article

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