Development and in vitro characterization of neuromedin U analogues

Chronic stress is a predominant risk factor for a variety of psychiatric disorders like depression, anxiety disorders and epilepsy. Endogenous systems which regulate the stress response are interesting targets for the development of novel treatments for stress-related disorders. In this study we focus on neuromedin U (NMU), a neuropeptide regulator of the stress response via top-down control of the hypothalamus-pituitary-adrenal axis. NMU exerts its biological effects via two G protein-coupled receptors, NMUR1 and NMUR2. NMUR1 is mostly found in the periphery whereas the receptor of our interest, NMUR2, is most abundant in the central nervous system. The purpose of this study is to develop new peptidergic selective NMUR2 antagonists which are enzymatically stable and blood-brain-barrier (BBB) permeable.
NMU-8, a natural occurring form of NMU in certain species, is taken as lead molecule for the synthesis of new analogues. The NMU-ligands are synthesized via solid phase peptide synthesis under classical conditions on rink amide polystyrene resin. A first batch of analogues is prepared on basis of the available structure-activity relationships. The in vitro characterization of these peptides is performed by an inositol phosphate accumulation assay.
The results of this in vitro characterization of our ligands are not always consistent with the available literature, but EC50 values of a similar magnitude are found for NMU-8. Moreover, our experiments revealed that acetylation of the N-terminus leads in general to an increase of the relative activity compared to the non-acetylated ligand. In conclusion, further research is needed to synthesize a NMUR2 selective, enzymatically stable and BBB permeable ligand.
An De Prins is funded by a Ph.D grant of the Agency for Innovation by Science and Technology in Flanders (IWT).