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 HEK293_mNPSR 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 [^<i>t</i>Bu-d-Gly⁵]NPS.