HJ-006: A Non-Hallucinogenic Synaptogenic Compound with Rapid and Sustained Antidepressant Efficacy
L. Zeng, Y. Chen, Y. Liu, Y. GengIntroduction
Current antidepressants (SSRIs/SNRIs) face limitations including delayed onset (4–6 weeks) and modest efficacy (~50% response rates), while serotonergic psychedelics show rapid antidepressant potential via 5-HT2A agonism and synaptic plasticity but are hindered by hallucinogenic activity and 5-HT2B-mediated cardiotoxicity.
Objectives
To address these challenges, we characterize HJ-006, a novel synaptogenic agent, designed to promote neuroplasticity without hallucinogenic or safety liabilities, and antidepressant efficacy.
Methods
Efficacy was evaluated with head twitch response (HTR) in mice (predictive of hallucinogenic activity), and established in vivo models (Forced Swim Test [FST], Tail Suspension Test [TST], Sucrose Preference Test [SPT] in Chronic Unpredictable Mild Stress [CUMS] and corticosterone-induced depression). Safety was evaluated via Conditioned Place Preference (CPP), neurite outgrowth/synaptogenesis assays, multielectrode array (MEA) recordings in CORT-damaged hippocampal neurons, cardiovascular monitoring (non-human primate ECG), and pharmacokinetic profiling.
Results
HJ-006 is an orally active, brain penetrant, small molecule. In vitro, HJ-006 showed significant effects on neurite-outgrowth and synaptogenesis in primary cultures of rat cortical neurons. It demonstrated rapid (30 min post-single dose) FST antidepressant effects in corticosterone-induced depression and reversed CUMS-induced deficits in FST, TST, and SPT, with efficacy sustained ≥8 days, with no hallucinogenic behavior (HTR-negative). Safety profiles included no CPP rewarding effects, enhanced dendritogenesis/synaptogenesis in cortical neurons, rescued CORT-impaired hippocampal activity (30 nM, 15 min post-treatment), 5-HT2B antagonist activity (Ki = 2.18 nM, IC50 = 272.8 nM), favorable brain penetration, CYP3A4 metabolism, no cardiovascular signals in primates, and a 40× safety margin in 14-day toxicity studies.
Conclusions
HJ-006 is a first-in-class non-hallucinogenic neuroplastogen with rapid, sustained antidepressant-like efficacy and improved safety, supporting its potential as a transformative depression treatment.
Disclosure of Interest
None Declared