Intranasal Administration of a Neuromedin-U Receptor 2-Specific Peptide Agonist for Obesity Treatment: Effect of the Stability on Brain Delivery

Neuromedin U (NMU) is a neuropeptide that was first identified in porcine spinal cord and exhibits diverse biological activities. It serves as an endogenous ligand for the human Neuromedin U receptor 2 (NMUR2), which is expressed exclusively in the hypothalamus. Because NMUR2 is involved in the regulation of appetite suppression and energy metabolism, it is considered a promising target for obesity treatment. CPN is a medium-sized peptide with selective agonistic activity against NMUR2. In this study, we evaluated the effect of peptide stability on brain delivery and the pharmacological effects after intranasal administration of two CPNs (CPN-116 and CPN-219) with different in vitro stabilities. The results of in vitro stability studies showed that both CPNs were more stable in the cerebrospinal fluid (CSF) than in the plasma and that the stability of CPN-219 in the serum, CSF, brain, and nasal cavity was better than that of CPN-116. For both CPNs, brain concentrations were higher in the nasal administration group than in the intraperitoneal administration group, and weight gain was also suppressed in the nasal administration group compared to the control group. Furthermore, both brain delivery and suppression of weight gain after nasal administration of CPN-219, which has good in vitro stability, were superior to those of CPN-116. It is evident that the stability of the peptide is an important factor for the direct delivery of peptides into the brain by intranasal administration.