Abstract
Neuropeptide S (NPS) is the last neuropeptide identified via reverse pharmacology techniques. NPS selectively binds and activates a previous orphan GPCR, now named NPSR, producing intracellular calcium mobilization and increases in cAMP levels. Biological functions modulated by the NPS/NPSR system include anxiety, arousal, locomotion, food intake, memory, and drug addiction. The primary sequence of NPS (in humans SFRNGVGTGMKKTSFQRAKS) is highly conserved among vertebrates especially at the N‐terminus. Ala‐ and D‐scan studies demonstrated that this part of the molecule is crucial for biological activity. Focused structure–activity studies performed on Phe^2^, Arg^3^, and Asn^4^ confirmed this indication and revealed the chemical requirements of these positions for NPSR binding and activation. The sequence Gly^5^‐Val^6^‐Gly^7^ seems to be important for shaping the bioactive conformation of the peptide. Structure–activity studies on Gly^5^ enabled identification of the first generation of peptidergic NPSR pure antagonists including [D‐Cys(tBu)^5^]NPS and [D‐Val^5^]NPS whose antagonist properties were confirmed in vivo. Finally, the pharmacological features of substituted bicyclic piperazine molecules (e.g. SHA 68 (3‐oxo‐1,1‐diphenyl‐tetrahydro‐oxazolo[3,4‐a]pyrazine‐7‐carboxylic acid 4‐fluoro‐benzylamide) were recently published making available the first generation of nonpeptide NPSR antagonists. The use in future studies of NPSR antagonists will be of paramount importance for understanding which biological functions are controlled by the NPS/NPSR system and for defining the therapeutic potential of selective NPSR ligands. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 5, 751–777, 2010