Exploring neurokinin-1 receptor antagonism for depression with structurally differentiated inhibitors.

The neurokinin-1 receptor (NK1R) has been investigated as a potential target for major depressive disorder owing to its role in stress regulation and neuroinflammation. However, clinical trials of NK1R antagonists have yielded inconsistent results, leaving it unclear whether these outcomes reflect limitations of NK1R as a therapeutic target or shortcomings inherent to the clinical candidates tested. The majority of previously developed NK1R antagonists contain a 3,5-bis-trifluoromethylphenyl moiety, which enhances receptor binding but may also influence drug metabolism, pharmacokinetics or receptor interactions, potentially affecting therapeutic efficacy. Whether structurally distinct NK1R antagonists exhibit different antidepressant potential remains an open question. Here we used computational approaches to identify NK1R antagonists lacking the 3,5-bis-trifluoromethylphenyl group and evaluated their effects in preclinical models of depression. Several compounds exhibited NK1R antagonistic activity and reduced depressive-like behaviors, with compound #15 demonstrating the most pronounced effects. Molecular docking and molecular dynamics simulations revealed a distinct binding mode for compound #15, characterized by a hydrogen bond interaction with Asn109 and π-π stacking with His197, suggesting structural differences that may influence NK1R modulation. These findings support the potential of structurally diverse NK1R antagonists to modulate behavior and neuroinflammatory responses in preclinical models. While the relevance of these structural differences to clinical outcomes remains to be determined, our results provide a preliminary framework for further investigation of chemically novel NK1R antagonists in the context of major depressive disorder.