HBK-10, a multimodal compound, selectively blocks 5-HT1A receptor-mediated β-arrestin recruitment and mitigates memory deficits in mice

While current antidepressants tackle depressive symptoms, they often fall short in addressing cognitive deficits associated with depression. Expanding upon our previous study on HBK-10, a multimodal compound targeting 5-HT1A receptors and demonstrating antidepressant-like properties, we now aim to investigate its procognitive potential and the underlaying mechanisms.First, we evaluated the influence of HBK-10 on ß-arrestin recruitment using CHO-K1 cells expressing the 5-HT1Areceptor. Subsequently, we conducted the Morris water maze test, employing the NMDA receptor antagonist MK-801 to induce memory impairments in mice. Following the behavioral test, we collected mouse hippocampi and prefrontal cortex tissues to assess the levels of signaling proteins using ELISA.HBK-10 selectively inhibited ß-arrestin recruitment after binding to the 5-HT1A receptor. In the Morris water maze, it effectively reversed spatial memory deficits by reducing latency to find the platform on days 5 and 6 at all doses. Notably, on the last day of the experiment, animals previously treated with HBK-10 at a dose of 2.5 mg/kg exhibited a significant reversal of cognitive impairments. Additionally, HBK-10 upregulated BDNF levels in both the hippocampus and prefrontal cortex of mice administered with a dose of 2.5 mg/kg.Our study reveals HBK-10's functional selectivity at the 5-HT1A receptor, specifically in ß-arrestin recruitment, and demonstrates its procognitive potential, possibly mediated through BDNF upregulation. With dual properties of antidepressant-like and memory enhancement, HBK-10 emerges as a promising drug candidate for depression treatment.This study was financed by the National Science Centre, Poland (grant number 2021/05/X/NZ7/00719) and Jagiellonian University Medical College (grant number N42/DBS/000329).