Development of Novel Estradiol-Indole Hybrids Targeting SERT and ERβ as Potential Antidepressants

Major depressive disorder (MDD) remains a global concern, with current treatments often showing delayed or limited efficacy. This research describes the development of novel estradiol-indole hybrids designed to inhibit the Serotonin Transporter (SERT) and activate the Estrogen receptor β (ERβ). Among 18 synthesized compounds, I₁₁ exhibited potent SERT inhibition (IC₅₀ = 16.92 ± 1.71 nM), strong ERβ agonism (EC₅₀ = 3.66 ± 0.55 nM, approximately 6-fold selectivity over ERα), and favorable oral absorption and brain penetration. Notably, I₁₁ reduced immobility in forced swim and tail suspension tests in chronic unpredictable mild stress (CUMS) mice and improved social interaction while reducing inactivity in chronic social defeat stress (CSDS) models. Consistent with coordinated involvement of ERβ signaling and SERT regulation, I₁₁ increased hippocampal serotonin levels and altered ERβ/SERT expression and downstream markers such as phosphorylated cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF). These results position I₁₁ as a promising dual-target antidepressant candidate with superior efficacy.