A team of South Korean researchers says the long-dismissed neurokinin-1 receptor (NK1R) could still hold the key to new antidepressants—if approached with smarter chemistry.

 

For decades, NK1R drew attention as a potential target for major depressive disorder. Early studies offered hope, but drugs like aprepitant ultimately failed in clinical trials, leaving scientists skeptical about whether NK1R itself was a viable pathway.

 

Now, researchers at Korea University report a breakthrough: by redesigning NK1R antagonists, they restored antidepressant-like effects in mice. Using machine-learning-guided screening, the team identified compounds that avoid chemical features found in earlier failures. The lead candidate reduced depressive-like behavior and brain inflammation in mouse models of stress- and inflammation-induced depression—without affecting locomotion.

 

“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,” said Professor Hong-Rae Kim.

 

The researchers removed a chemical group commonly used in previous NK1R drugs and replaced it with a novel molecular scaffold. Using computational screening, they analyzed millions of molecules and highlighted compound #15 for its potent activity. The compound binds NK1R through a unique interaction profile, suggesting that the right molecular design can revive a previously abandoned target.

 

The implications go beyond depression. Inflammation is increasingly linked to poor antidepressant response, and these structurally novel NK1R antagonists may eventually be explored for inflammation-associated depression.

 

“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,” Professor Hong-Rae added.