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 Gly<sup>5</sup> with d-amino acids generates NPSR antagonists. Eleven [d-Xaa<sup>5</sup>]NPS derivatives were synthesized and pharmacologically tested measuring [Ca<sup>2+</sup>]<sub>i</sub> in HEK293<sub>mNPSR</sub> cells. The results confirmed that the [d-Xaa<sup>5</sup>] substitution promotes antagonist activity with potency inversely related to the side chain size and allowed identification of the novel potent NPSR peptide antagonist [<sup><i>t</i></sup>Bu-d-Gly<sup>5</sup>]NPS.