Further Studies at Neuropeptide S Position 5: Discovery of Novel Neuropeptide S Receptor Antagonists

Neuropeptide S (NPS) regulates various biological functions by activating the NPS receptor (NPSR). Previous studies demonstrated that the substitution of Gly5 with d-amino acids generates NPSR antagonists. Eleven [d-Xaa5]NPS derivatives were synthesized and pharmacologically tested measuring [Ca2+]i in HEK293mNPSR cells. The results confirmed that the [d-Xaa5] substitution promotes antagonist activity with potency inversely related to the side chain size and allowed identification of the novel potent NPSR peptide antagonist [tBu-d-Gly5]NPS.