文摘
Neuropeptide S (NPS) is the endogenous ligand of the previously orphan G-protein coupled receptor nownamed NPSR. The NPS-NPSR receptor system regulates important biological functions such as sleep/waking, locomotion, anxiety and food intake. Recently, exhaustive Ala scan and D-amino acid scan studies,together with systematic N- and C-terminal truncation, led to the identification of key residues for biologicalactivity. Because conformational preferences might also play an important role, we undertook a detailedconformational analysis of NPS and several analogues in solution. We show that helicity induced bysubstitution of three flexible residues in the 5-13 regulatory region abolishes biological activity. A parallelpharmacological and conformational study of single and multiple substitutions of glycines 5, 7, and 9 showedthat helicity can be tolerated in the C-terminal part of the peptide but not around Gly7. The identification ofhNPSR partial agonists heralds the possibility of designing pure NPS receptor antagonists.
