HBK-15 bypasses BDNF via ERK1/2-biased 5-HT1A receptor signaling to deliver a rapid antidepressant-like effect

Abstract Rapid-onset antidepressants hold transformative potential for treating affective and cognitive symptoms of depression, yet their mechanisms remain incompletely understood. Serotonin receptors orchestrate emotional and cognitive regulation, but current treatments poorly target their intracellular signaling. Here, we characterize HBK-15, a multi-target aminergic ligand, as a functionally selective compound that biases intracellular signaling at 5-HT1A and 5-HT₇ receptors. HBK-15 acts as a partial agonist at the ERK1/2 arm of the 5-HT1A receptor while blocking β-arrestin recruitment, cAMP inhibition, and calcium mobilization; at 5-HT₇ receptors, it preserves cAMP signaling but blocks β-arrestin recruitment. A single dose of HBK-15 reversed depressive- and cognitive-like deficits in two mouse strains subjected to chronic stress, engaging ERK1/2-linked kinases and plasticity-related signaling in the prefrontal cortex. Pharmacological blockade experiments showed that ERK1/2, but not PKA, signaling in the medial prefrontal cortex is required for HBK-15’s behavioral effects. Notably, HBK-15 retained antidepressant-like efficacy in mice carrying the human BDNF Val66Met polymorphism, a translational model characterized by impaired activity-dependent BDNF release, increased depression vulnerability, and reduced treatment responsiveness. The absence of cognitive rescue in this context uncovers a layered mechanism: ERK1/2 signaling is required for both behavioral domains, but BDNF-dependent pathways appear critical for cognitive restoration. These findings position HBK-15 as a mechanistically distinct compound with rapid behavioral efficacy, offering a prototype for signaling-driven strategies in next-generation antidepressant development.