Unanticipated Characteristics of a Selective, Potent Neuromedin-U Receptor 2 Agonist

Neuromedin-U (NMU)mediates several physiological functions viaits two cognate receptors, NMUR1 and NMUR2. Disentangling the individualroles of each receptor has largely been undertaken through the useof transgenic mice bearing a deletion in one of the two receptorsor by testing native molecules (NMU or its truncated version NMU-8)in a tissue-specific manner, in effect, taking advantage of the distinctreceptor expression profiles. These strategies have proved quite usefuldespite the inherent limitations of overlapping receptor roles andpotential compensatory influences of germline gene deletion. Withthese considerations in mind, the availability of potent, selectiveNMU compounds with appropriate pharmacokinetic profiles would advancethe capabilities of investigators undertaking such efforts. Here,we evaluate a recently reported NMUR2-selective peptide (compound 17) for its in vitro potency (mouse and human), binding affinity,murine pharmacokinetic properties, and in vivo effects. Despite beingdesigned as an NMUR2 agonist, our results show compound 17 unexpectedly binds but does not have functional activity on NMUR1,thereby acting as an R1 antagonist while simultaneously being a potentNMUR2 agonist. Furthermore, evaluation of compound 17 across all known and orphan G-protein-coupled receptors demonstratesmultiple receptor partners beyond NMUR2/R1 binding. These propertiesneed to be appreciated for accurate interpretation of results generatedusing this molecule and may limit the broader ability of this particularentity in disentangling the physiological role of NMU receptor biology.