For decades, scientists have investigated the neurokinin-1 receptor (NK1R) as a potential target for treating major depressive disorder. Early studies suggested promise, but enthusiasm faded after clinical trials of drugs such as aprepitant failed to show clear benefits, raising doubts about whether NK1R itself was a viable antidepressant target.
Now, researchers from Korea University report that the problem may not lie with the target, but with the chemistry. In a new study led by Professors Hyeijung Yoo, Hong-Rae Kim, and Hyun Kim, published in Experimental & Molecular Medicine on November 28, 2025, the team shows that redesigning the molecular structure of NK1R antagonists can restore antidepressant-like effects in preclinical models. By removing a chemical group commonly found in earlier drug candidates and replacing it with a structurally distinct scaffold, the researchers identified new compounds that reduced depressive-like behavior and neuroinflammation in mice. Prof. Hong-Rae informed, "Our findings suggest that the structurally distinct antagonists identified in this study exhibit antidepressant-like effects, providing renewed evidence for further exploration of NK1R antagonism as a therapeutic strategy for MDD."
Using machine-learning-based virtual screening, the team analyzed millions of molecules to identify NK1R antagonists lacking the commonly used 3,5-bis-trifluoromethylphenyl (TFMP) group, which may contribute to inconsistent clinical outcomes. Several candidates were tested, with compound #15 showing strong activity. In mouse models of stress- and inflammation-induced depression, it reduced depressive-like behaviors and neuroinflammation without affecting locomotion, while binding the NK1 receptor through a distinct interaction profile.
The study has implications beyond depression. Because inflammation is increasingly recognized as a contributor to poor antidepressant response in some patients, structurally novel NK1R antagonists could eventually be explored for inflammation-linked depression subtypes. Prof. Hong-Rae concluded, "Our results provide a foundation for optimizing NK1R antagonists and underscore the importance of structural diversity, which could lead to new therapeutic options in treatment-resistant or inflammation-associated depression."
The work also highlights a broader strategy for drug discovery: revisiting previously abandoned targets using modern computational design and biological validation.
