Researchers from Korea University have proposed a new approach to treating major depressive disorder (MDD), drawing renewed attention to a long-studied but previously overlooked molecular target: the neurokinin-1 receptor (NK1R).

This receptor has long been considered a promising candidate for the development of antidepressants, but early attempts to create effective drugs, such as aprepitant, did not yield convincing results in clinical trials, prompting many research teams to abandon the idea of using it.

A new study published in the journal Experimental & Molecular Medicine, however, shows that the target itself may have been promising, but previous compounds did not have the optimal chemical structure.

The research team, led by Professors Hyeijung Yoo, Hong-Rae Kim and Hyun Kim, showed that reshaping the molecular structure of NK1R antagonists—that is, removing a familiar chemical moiety and replacing it with a new backbone—resulted in compounds that reduced depression-like behaviors and neuroinflammation in preclinical mouse models. These effects suggest that the correct molecular interaction with the receptor could restore antidepressant properties lost in previous versions of the drug.

The researchers used computational screening and machine learning to analyze millions of molecules and identify those that bind to NK1R through a novel pathway, bypassing the limitations of previous candidates. One of the lead compounds, tentatively named “compound #15,” has shown the ability to reduce signs of depression in induced mouse models of stress and inflammation without significantly affecting the animals’ normal functioning.

The study authors emphasize that the structural diversity of chemical compounds is important for reviving previously rejected psychopharmacological targets.

This discovery may shed light on new strategies for treating depression, especially in cases where traditional antidepressants are ineffective.