Study on Neurokinin 1 Receptor and Chemotherapy Side Effects

Importance of NK1 Receptor in Cancer Treatment

A recent study focusing on the neurokinin 1 receptor (NK1R) may play a significant role in developing medications to alleviate the adverse effects of chemotherapy. Currently, many cancer treatments are associated with side effects, particularly nausea and vomiting, collectively known as chemotherapy-induced nausea and vomiting (CINV). The unpleasant sensations experienced by patients are mediated by the NK1R class of receptors. For decades, efforts have been made to pharmacologically target these receptors to mitigate chemotherapy side effects.

Current Treatments Targeting NK1R

This research has led to the creation of drugs such as Aprepitant and Netupitant, which are now utilized to target NK1R and reduce the side effects associated with cancer chemotherapy. Additionally, the NK1R is implicated in various pathological conditions, including gastrointestinal disorders, inflammation, migraine, depression, and asthma. The ongoing development of chemical compounds aimed at this receptor has generated excitement among researchers, who hope to create further anti-nausea medications and treatments for diseases influenced by NK1R.

Research Findings from the University of Zurich

Researchers from the University of Zurich in Switzerland have successfully determined the three-dimensional structure of the NK1R when bound to the drugs Aprepitant and Netupitant. They also isolated the receptor when it was bound to a test compound, CP-99,994, which emerged from a large-scale screening of thousands of chemicals for NK1R inhibitory activity. Their findings were published in the journal *Nature Communications*.

Structural Analysis and Binding Mechanism

The structural analysis indicated that both Aprepitant and Netupitant bind the NK1R with equal affinity as CP-99,994. However, the former two drugs exhibit a longer retention time on the receptor, contributing to their effectiveness. The authors identified a mechanism behind this phenomenon: the clinically approved inhibitors alter the receptor’s structure upon binding, which facilitates the “trapping” of the inhibitors on its surface. In contrast, the test compound binds effectively but fails to induce a similar structural change, resulting in its release from the receptor.

Implications for Future Drug Development

The authors propose that insights into the structure of the NK1R could expedite the discovery of new anti-nausea medications aimed at managing chemotherapy side effects and treating conditions influenced by NK1R.

Reference

Schöppe, J., Ehrenmann, J., Klenk, C., Rucktooa, P., Schütz, M., Doré, A. S., & Plückthun, A. (2019). Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists. *Nature Communications*, 10(1), 17. doi:10.1038/s41467-018-07939-8