Chronic stress is a predominant risk factor for a variety of psychiatric and neurological disorders such as depression, anxiety and epilepsy. Endogenous systems which regulate the stress response are interesting tartgets for the development of novel treatments for these 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 NMUR2, the receptor of our interest, is most abundant in the central nervous system (Brighton et al, 2004). 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 (H-Tyr-Phe-Leu-Phe-Arg-Pro-Arg-Asn-NH2), a natural occuring form of NMU, 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. Mainly two types of modifications are performed, namely chirality switches and the introduction of different N-capping groups. The in vitro characterization of these peptides is performed by an inositol phosphate accumulation assay. The results of this in vitro characterization present EC50 values of a similar magnitude as 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. This first generation of NMU analogues includes peptides which could possibly act as antagonists on both NMURs, as no inositol accumulation was detected up to 10-6M. On basis of the performed assay it cannot be concluded that antagonism is indeed present. Some peptides of the first generation of NMU analogues are partial agonists for both NMURs, certain amongst them with EC50 values of comparable magnitude as NMU-8. Further research is needed to synthesize a NMUR2 selective, enzymatically stable and BBB permeable ligand.