Discovery of a Pentapeptide Antagonist to Human Neuromedin U Receptor 1

Neuromedin U (NMU) activates two types of receptors (NMUR1 and NMUR2), and the former is mainly expressed in the peripheral tissues, including the intestinal tract and lung tissues. Since NMUR1 contributes to the promotion of type 2 inflammation in these tissues, it is a potential target to suppress inflammatory responses. However, promising antagonist candidates for human NMUR1 have not yet been developed. Here we successfully identified pentapeptide antagonist 9a through a structure–activity relationship study based on hexapeptide lead 1. Its antagonistic activity against human NMUR1 was 10 times greater than that against NMUR2. This is a breakthrough in the development of NMUR1-selective antagonists. Although 9a was relatively stable in the plasma, the C-terminal amide was rapidly degraded to the carboxylic acid by the serum endopeptidase thrombin, which acted as an amidase. This basic information would aid in sample handling in future biological evaluations.