Mice experiencing stress surrender more quickly. They cease swimming, they stop fighting. This serves as a rudimentary indicator of despair, yet for years, it has been a method for researchers to evaluate antidepressants. And for years, one potentially effective brain target consistently failed this assessment in humans, despite functioning effectively in rodents.
The target in question was the neurokinin-1 receptor, or NK1R. By the early 2000s, following the failure of drugs like aprepitant in clinical trials, many researchers determined that the biological basis was flawed. Scientists at Korea University now assert that the chemistry was at fault instead.
In a study featured in Experimental & Molecular Medicine, the team reveals that novel NK1R inhibitors with different structures lessen depressive behaviors and brain inflammation in mice. The solution was not to abandon the target, but rather to discard a chemical characteristic shared by nearly all prior drugs.
One Scaffold, Many Failures
Most previous NK1R antagonists included a component known as a 3,5-bis-trifluoromethylphenyl group. This structural motif allows drugs to bind the receptor strongly, but it might also lead to complications elsewhere, influencing how the body processes substances or how they react with other proteins.
The Korea University team completely removed it. By employing machine learning to sift through millions of molecules, they pinpointed candidates with fundamentally unique structures. One candidate, referred to as compound #15, was particularly notable.
This compound interacted with NK1R in a novel manner and demonstrated efficacy across various mouse models. Mice subjected to social isolation, restraint stress, or inflammatory challenges exhibited reduced immobility in behavioral assessments. They were less likely to give up. Concurrently, indicators of neuroinflammation decreased in brain regions associated with mood, including the frontal cortex and hippocampus.
This anti-inflammatory effect is significant. Chronic inflammation is one factor contributing to why certain patients do not respond to standard antidepressants like SSRIs.
“Our results indicate that the structurally distinct antagonists identified in this research display antidepressant-like effects, providing renewed evidence for further investigation of NK1R antagonism as a treatment strategy for MDD,” states Hong-Rae Kim.
A Different Fit
Computer simulations showed that compound #15 creates a unique hydrogen bond within the receptor pocket, a feat previous drugs could not achieve. This altered interaction may clarify why it produces effects that the earlier equivalents did not.
The study does not propose that NK1R antagonists are ready for clinical use. The findings are solely derived from animal models, and the transition to humans has historically proven to be a challenging phase for many depression medications. The safety profile and pharmacokinetics remain undetermined. Whether these compounds would outperform current treatments remains uncertain.
However, this research recontextualizes a 20-year-old disappointment. When a drug class fails in clinical settings, it’s tempting to presume the biological target was illusory. This indicates that the molecules themselves could have been the constraining element.
For the field of depression research, that distinction is crucial. Progress might sometimes arise not from finding new targets, but from discovering how to better examine existing ones using improved chemistry.
DOI: https://doi.org/10.1038/s12276-025-01576-0
If our reporting has informed or inspired you, please consider making a donation. Every contribution, no matter the size, empowers us to continue delivering accurate, engaging, and trustworthy science and medical news. Independent journalism requires time, effort, and resources—your support ensures we can keep uncovering the stories that matter most to you.
Join us in making knowledge accessible and impactful. Thank you for standing with us!