title: Synthesis and biological activity of human neuropeptide S analogues modified in position 2.
abstract: Neuropeptide S (NPS) has been identified as the endogenous ligand of a previously orphan receptor now named NPSR. Previous studies demonstrated that the N-terminal sequence Phe (2)-Arg(3)-Asn(4) of the peptide is crucial for biological activity. Here we report on a focused structure-activity study of Phe(2) which has been replaced with a series of coded and noncoded amino acids. Thirty-one human NPS analogues were synthesized and pharmacologically tested for intracellular calcium mobilization by using HEK293 cells stably expressing the mouse NPSR. The results of this study demonstrated the following NPS position 2 structure-activity features: (i) lipophilicity but not aromaticity is crucial, (ii) both the size of the chemical moiety and its distance from the peptide backbone are important for biological activity, and (iii) this position plays a role in both receptor binding and activation, since [4,4'-biphenyl-Ala(2)]hNPS behaved as a partial agonist.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Pharmacology and Italian Institute of Neuroscience, University of Ferrara, via Fossato di Mortara 19, Ferrara, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Camarda
authors.forename: Claudio
authors.initials: C
authors.lastname: Trapella
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calo
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Anna
authors.initials: A
authors.lastname: Rizzi
authors.forename: Chiara
authors.initials: C
authors.lastname: Ruzza
authors.forename: Stella
authors.initials: S
authors.lastname: Fiorini
authors.forename: Erika
authors.initials: E
authors.lastname: Marzola
authors.forename: Rainer K
authors.initials: RK
authors.lastname: Reinscheid
authors.forename: Domenico
authors.initials: D
authors.lastname: Regoli
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D051379:Mice; D009479:Neuropeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010649:Phenylalanine / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D009479:Neuropeptides; D043562:Receptors, G-Protein-Coupled; C506531:neuropeptide S, human; D010649:Phenylalanine; D002118:Calcium