Korea University Researchers Pioneer Novel Approach to Combat Depression with NK1 Receptor Inhibitors

Reviving Depression Treatment: A Breakthrough from Korea University

Researchers at Korea University have breathed new life into depression treatment strategies by redesigning neurokinin-1 receptor (NK1R) antagonists, offering promising results in animal models. This innovative approach aims to restore antidepressant-like effects that had previously lost their momentum due to earlier clinical trial failures.

Insight into NK1R Antagonists

For many years, NK1R has been under scrutiny as a potential target for treating major depressive disorder (MDD). Initial studies showcased its potential; however, enthusiasm waned as drugs like aprepitant failed to deliver desirable clinical outcomes. The perception shifted, leading many to doubt the viability of NK1R as a target for antidepressant therapy.

However, recent findings from researchers at Korea University, led by Professors Hyeijung Yoo, Hong-Rae Kim, and Hyun Kim, challenge these notions, indicating that previous failures might stem not from the target itself but the drug chemistry. Their latest study, which was published in Experimental Molecular Medicine, reveals that with a structural redesign of NK1R antagonists, it’s possible to regain the antidepressant-like properties in preclinical trials.

The Novel Approach

Employing machine-learning-guided screening, the research team meticulously analyzed millions of molecules to discover NK1R antagonists that exclude a commonly utilized chemical group known as the 3,5-bis-trifluoromethylphenyl (TFMP) group. This particular modification aims to eliminate inconsistencies plaguing past clinical trials. Through their diligent screenings, the researchers identified a lead compound, referred to as compound #15, that exhibited impressive results, demonstrating enhanced interaction profiles with the NK1 receptor while minimizing locomotive side effects.

In extensive mouse models of stress- and inflammation-induced depression, compound #15 significantly diminished depressive-like behaviors and neuroinflammation, indicating a return to effective antidepressant outcomes. This research not only suggests the NK1R target remains relevant but also highlights the potential of innovative molecular designs in enhancing therapeutic efficacy.

Implications Beyond Depression

The implications of this research transcend the realm of depressive disorders. As inflammation has emerged as a pertinent factor in the subpar responses to traditional antidepressants in certain patients, structurally distinct NK1R antagonists might serve as a promising treatment avenue for inflammation-associated depression types. Professor Hong-Rae emphasizes that this study lays a strong foundation for optimizing NK1R antagonism as a therapeutic strategy, advocating for a focus on structural diversity in drug discovery.

Conclusion

Korea University’s pioneering research showcases a significant step forward in depression treatment methodologies by reviving a previously overlooked drug target through modern computational designs and biological validation. The insights derived from this study provide a compelling argument for revisiting abandoned targets with enhanced molecular designs, laying the groundwork for novel therapies in treatment-resistant or inflammation-related depressive disorders.

Reference

The original study titled "Exploring neurokinin-1 receptor antagonism for depression with structurally differentiated inhibitors" was published in Experimental Molecular Medicine and can be accessed through DOI 10.1038/s12276-025-01576-0. For further information, visit the Korea University College of Medicine website.